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CN117881668A - Compounds based on isoindoline-substituted glutarimide skeleton and their applications - Google Patents

Compounds based on isoindoline-substituted glutarimide skeleton and their applications Download PDF

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Publication number
CN117881668A
CN117881668A CN202380010568.9A CN202380010568A CN117881668A CN 117881668 A CN117881668 A CN 117881668A CN 202380010568 A CN202380010568 A CN 202380010568A CN 117881668 A CN117881668 A CN 117881668A
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methyl
dione
biphenyl
piperidine
oxoisoindolin
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杨小宝
孙仁红
周跃东
赵宝寅
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Biaoxin Biomedical Technology Shanghai Co ltd
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Biaoxin Biomedical Technology Shanghai Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本公开涉及式(I)的化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物及其应用。本公开还涉及包含作为活性成分的式(I)的化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物的药物组合物及其应用。本公开设计合成的一系列化合物能有效地预防和/或治疗与cereblon蛋白相关的疾病或病症。 The present disclosure relates to compounds of formula (I) or salts thereof, enantiomers, stereoisomers, solvates, polymorphs and their applications. The present disclosure also relates to pharmaceutical compositions comprising compounds of formula (I) or salts thereof, enantiomers, stereoisomers, solvates, polymorphs as active ingredients and their applications. A series of compounds designed and synthesized by the present disclosure can effectively prevent and/or treat diseases or conditions associated with cereblon protein.

Description

Compound based on isoindoline substituted glutarimide skeleton and application thereof Technical Field
The present disclosure relates to compounds of formula (I) or salts, enantiomers, diastereomers, isotopically enriched analogs, solvates, prodrugs or polymorphs thereof and uses thereof, particularly for prophylaxis and use thereofAnd/or the treatment of a disease or condition associated with the cereblon protein (CRBN).
Background
Thalidomide, lenalidomide and other phthalimide immunomodulators (IMiDs) have remarkable curative effects on treating multiple myeloma and autoimmune diseases, but until 2010, the direct binding protein of the thalidomide, lenalidomide and other phthalimide immunomodulators (IMiDs) is not identified as E3 ubiquitin ligase Cereblon (CRBN), and then the fact that the medicines act as molecular gel through inducing interaction of transcription factors IKZF1/3 and CRBN protein so as to cause ubiquitination degradation of the medicines is proved. Compared with the traditional small molecule inhibitor, the molecular mucin degradation drug has the advantage of natural mechanism: the latter is acted by occupying the functional domain of the target protein for a long time to inhibit the function, and the protein degradation medicine is directly degraded to remove the whole target protein, so that the medicine effect is far greater than that of the traditional small molecule inhibitor, the target can be targeted to a 'non-patent medicine' target, the requirement on the binding force is low, the catalytic amount is low, and the clinical drug resistance problem of the traditional small molecule can be overcome. And the molecular gel degradation agent has small molecular weight and good pharmaceutical property, so the research and development of the medicine are highly valued. Based on CRBN E3 ubiquitin ligase and molecular gel degradation mechanism, a series of compounds have been developed, such as Pomalidomide on the market and BASEMERIZA BASED (BMS) from BASED on the clinical trial, CC-122, CC-220, CC-90009, CC-99282 and CC-92480, DKY709 from Novartis (Novartis) and CFT7455 from C4 Therapeutics. The degradation substrates of the molecular gel are also expanded from the originally discovered transcription factor IKZF1/3 to casein kinase 1 alpha (CK 1 alpha), zinc finger protein 91 (ZFP 91), translation factor GSPT1 and the like, and the degradation of the protein substrates can lead the molecular gel to exert the pharmacodynamic activities of immunoregulation, anti-inflammation, anti-tumor and the like. The molecular gel candidate compounds which are found at present are very limited, and the pathogenic proteins which can be used as degradation substrates for molecular gel development are various in theory, so that more pathogenic proteins are required to be degraded and knocked out through rationalized and diversified design development of more molecular gels, and the molecular gel candidate compounds are applied to the treatment of pathogenic protein related diseases.
The invention is based on the benzopentan diimide skeleton, and meets the requirements of clinical application by rationalizing the design and developing more novel, efficient, low-toxicity, stable in property and low in cost molecular gum degradation agents.
Disclosure of Invention
In view of the above, it is an object of the present disclosure to provide novel molecular gelatin protein degradation drugs, their uses, and methods of their use.
To achieve the above and other related objects, in one aspect, the present disclosure provides a compound of formula (I) or a salt, stereoisomer (including enantiomer, diastereomer), isotopically enriched analog, solvate, prodrug, or polymorph thereof:
wherein the method comprises the steps of
R b1 、R b2 、R b3 、R b4 And R b5 Each independently represents H, D or C 1-3 An alkyl group;
x represents C (O) or CH 2 ；
(R a ) n The benzene ring of formula (I) is optionally substituted with n R a Substitution, wherein R a Represents deuterium, halogen, hydroxy, mercapto, nitro, amino, cyano, optionally deuterated C 1-6 Alkyl, optionally deuterated C 1-6 Alkoxy, or halo C 1-6 Alkyl, and n represents an integer of 0, 1, 2, or 3; and
L 1 represents C (O), alkenylene, optionally substituted C 1-5 Alkylene, -ch=, optionally substituted C 6-10 arylene-C 1-5 Alkylene-, or N (R) c1 ) Wherein R is c1 Represents H or C 1-3 Alkyl, symbol represents a group X 1 Or L 1 represents-C (R) L1 R L2 ) -, wherein R is L1 、R L2 Together with the carbon atoms to which they are attached form an optionally substituted C 3-8 Cycloalkylene, or L 1 Representing a bond;
X 1 represents optionally substituted cycloalkylene, optionally substituted heterocyclylene or optionally substituted heteroarylene;
X 2 represents C (O), optionally substituted C 1-5 Alkylene, optionally substituted C 3-8 Cycloalkylene, optionally substituted C 1-2 alkylene-N (R) c2 )-、-N(R c2 ) -optionally substituted C 1-2 Alkylene, or N (R) c3 ) Wherein R is c2 And R is c3 Each independently represents H or C 1-3 Alkyl, or X 2 Representing a bond;
R a1 the following structure is shown:
wherein the method comprises the steps of
Ring A represents a heterocyclylene, cycloalkylene, arylene, or heteroarylene group, (R) d1 ) m1 Represents ring A optionally substituted by m1 radicals R d1 Substituted, m1 represents an integer of 0 to 10, each R d1 Independently represents deuterium, hydroxy, amino, mercapto, halogen, cyano, oxo, optionally deuterated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, halo C 1-6 Alkyl, C 1-4 alkyl-NH-, C 1-4 alkyl-NHC (O) -, C 1- 4 alkyl-C (O) NH-, or NH 2 -C 1-6 An alkylene group; and
ring B represents aryl, cycloalkyl, heterocyclyl, or heteroaryl, (R) d2 ) m2 Represents ring B optionally substituted by m2 radicals R d2 Substituted, m2 represents an integer of 0 to 10, each R d2 Independently represents deuterium, hydroxy, amino, mercapto, halogen, cyano, oxo, optionally deuterated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, halo C 1-6 Alkyl, C 1-4 alkyl-NH-, C 1-4 alkyl-NHC (O) -, C 1-4 alkyl-C (O) NH-, or NH 2 -C 1-6 An alkylene group;
wherein when L 1 X when representing a bond 1 Represents an optionally substituted nitrogen-containing bridged heterocyclyl; when X 2 When representing a bond, L 1 Not a key.
In another aspect, the present disclosure provides a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer (including enantiomer, diastereomer), solvate, isotopically enriched analog, prodrug, or polymorph thereof, and at least one pharmaceutically acceptable carrier.
In another aspect, the present disclosure also provides a kit or kit comprising: a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same.
In another aspect, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, prodrug, or polymorph thereof, for use as a medicament.
In another aspect, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer (including enantiomer, diastereomer), solvate, isotopically enriched analog, prodrug, or polymorph thereof, or a pharmaceutical composition of the disclosure, for use in treating or preventing a disease or disorder associated with a cereblon protein.
In another aspect, the present disclosure also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer (including enantiomer, diastereomer), solvate, isotopically enriched analog, prodrug or polymorph thereof, or the pharmaceutical composition of the disclosure, for the preparation of a medicament for treating or preventing a disease or disorder associated with the cereblon protein.
In another aspect, the present disclosure also provides a method of treating or preventing a disease or disorder associated with cereblon protein in a subject, comprising administering to the subject a therapeutically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer (including enantiomer, diastereomer), solvate, isotopically enriched analog, prodrug, or polymorph thereof, or the pharmaceutical composition.
Drawings
FIG. 1 is a study of the degradation of IKZF1/3 proteins and GSPT1 proteins by the compounds of the invention in human primary peripheral blood mononuclear cells (Human peripheral blood mononuclear cells, hBMC).
Detailed Description
The following detailed description is provided as an exemplary embodiment to assist those of ordinary skill in the art in understanding and practicing the present disclosure. It will be appreciated, however, that such description is not intended to limit the scope of the present disclosure, and that various modifications and changes may be made to the particular embodiments described in the present disclosure without departing from the spirit and scope of the present disclosure, which changes and modifications fall within the scope of the present disclosure as claimed.
I. Compounds of formula (I)
A compound of formula (I)
The present disclosure provides a compound of formula (I) or a salt (including pharmaceutically acceptable salts), stereoisomer (including enantiomers, diastereomers), solvate, isotopically enriched analog, prodrug, or polymorph thereof:
wherein the radicals R b1 、R b2 、R b3 、R b4 、R b5 、(R a ) n 、X、L 1 、X 1 、X 2 And R is a1 A compound of formula (I) as defined above in the various embodiments.
The present disclosure provides compounds of formula (I) or salts (including pharmaceutically acceptable salts), stereoisomers (including enantiomers), solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof having binding capacity for CRBN, facilitating recruitment of substrate proteins. The compounds of formula (I) of the present disclosure, or salts (including pharmaceutically acceptable salts), stereoisomers (including enantiomers), solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof, may also degrade substrate proteins (e.g., IKZF1/2/3/4 proteins, WEE1 proteins, CK1 alpha proteins, GSPT1 proteins, ZFP91 proteins, etc.). The compounds of formula (I) or salts (including pharmaceutically acceptable salts), stereoisomers (including enantiomers), solvates, isotopically enriched analogs, prodrugs or polymorphs thereof of the present disclosure have antitumor activity or excellent pharmacokinetic properties and are useful as therapeutic agents for oncological patients.
In some embodiments of the disclosure, R b1 、R b2 、R b3 、R b4 And R is b5 Same or different and each independently represents H, D or C 1-3 Alkyl (e.g., methyl, ethyl, or propyl). In some sub-embodiments of the disclosure, R b1 、R b2 、R b3 、R b4 And R is b5 The same or different and each independently represents H. In some sub-embodiments of the disclosure, R b1 、R b2 、R b3 、R b4 And R is b5 The same or different and each independently represents D. In some sub-embodiments of the disclosure, R b1 、R b2 、R b3 And R is b4 Each independently represents H, R b5 Representation H, D or C 1-3 Alkyl (e.g., methyl, ethyl, or propyl).
In some embodiments of the disclosure, X represents C (O).
In some embodiments of the disclosure, X represents CH 2 。
In some embodiments of the disclosure, (R) a ) n The benzene ring of formula (I) is optionally substituted with n R a Substitution, wherein R a Represents deuterium, halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, mercapto, nitro, amino, cyano, optionally deuterated C 1-6 Alkyl (e.g. optionally deuterated C 1-4 Alkyl or optionally deuterated C 1-3 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl), optionally deuterated C 1-6 Alkoxy (e.g. optionally deuterated C 1-4 Alkoxy or optionally deuterated C 1-3 Alkoxy radicalRadicals, e.g. methoxy, ethoxy, or propoxy), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), and n represents an integer of 0, 1, 2 or 3. In some sub-embodiments of the present disclosure, n represents an integer of 0. In some sub-embodiments of the present disclosure, n represents an integer of 1. In some sub-embodiments of the present disclosure, n represents an integer of 2. In some sub-embodiments of the present disclosure, n represents an integer of 3.
In some embodiments of the disclosure, (a) L 1 Represents C (O), alkenylene (e.g. C 2-8 Alkenylene, C 2-6 Alkenylene, C 2-4 Alkenylene or C 2-3 Alkenylene), optionally substituted C 1-5 Alkylene (e.g. optionally substituted C 1-4 Alkylene or optionally substituted C 1-3 Alkylene), -ch=, optionally substituted C 6-10 arylene-C 1-5 Alkylene- (e.g. optionally substituted C 6-10 arylene-C 1-3 Alkylene-), or N (R) c1 ) Wherein R is c1 Represents H or C 1-3 Alkyl (e.g. methyl, ethyl, or propyl), the symbol X represents a group X 1 Or L 1 represents-C (R) L1 R L2 ) -, wherein R is L1 、R L2 Together with the carbon atoms to which they are attached form an optionally substituted C 3-8 Cycloalkylene radicals (e.g. optionally substituted C 3-7 Cycloalkylene group); and/or (b) X 1 Represents optionally substituted cycloalkylene radicals (e.g. optionally substituted C 3-20 Cycloalkylene or optionally substituted C 3-15 Cycloalkylene), optionally substituted heterocyclylene (e.g., optionally substituted 4-to 20-membered heterocyclylene or optionally substituted 4-to 15-membered heterocyclylene), or optionally substituted heteroarylene (e.g., optionally substituted 5-to 20-membered heteroarylene or optionally substituted 5-to 15-membered heteroarylene).
In some of the present disclosureIn embodiments, (a 1) L 1 Represents C (O), C 2-6 Alkenylene (e.g. C 2-5 Alkenylene, C 2-4 Alkenylene or C 2-3 Alkenylene), optionally substituted C 1-5 Alkylene (e.g. optionally substituted C 1-4 Alkylene or optionally substituted C 1-3 Alkylene), -ch=, optionally substituted C 6-10 arylene-C 1-5 Alkylene- (e.g. optionally substituted C 6-10 arylene-C 1- 3 Alkylene-), or N (R) c1 ) Wherein R is c1 Represents H or C 1-3 Alkyl (e.g. methyl, ethyl, or propyl), the symbol X represents a group X 1 Wherein said C 1-5 Alkylene and said C 6-10 arylene-C 1-5 Alkylene groups are each independently optionally substituted with 1 to 10 (e.g., 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2, or 1) groups selected from D, optionally deuterated C 1-4 Alkyl (e.g. optionally deuterated C 1-3 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl), hydroxy, amino, mercapto, halogen (e.g., fluorine, chlorine, bromine, or iodine), cyano, C 1-4 Alkoxy (e.g. C 1-3 Alkoxy, e.g. methoxy, ethoxy, or propoxy), C 1-4 alkyl-NH- (e.g. C) 1-3 alkyl-NH-, e.g. CH 3 NH-、CH 3 CH 2 NH-or CH 3 CH 2 CH 2 NH-), halogenated C 1-4 Alkyl (e.g. halogenated C) 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)、NH 2 -C 1-4 Alkylene- (e.g. NH) 2 -C 1-3 Alkylene-, e.g. NH 2 CH 2 -、NH 2 CH 2 CH 2 -or NH 2 CH 2 CH 2 CH 2 -)、C 1-4 alkyl-NHC (O) - (e.g. C) 1-3 alkyl-NHC (O) -, e.g. CH 3 -NHC(O)-、CH 3 CH 2 NHC (O) -, or CH 3 CH 2 CH 2 -NHC(O)-)、C 1-4 alkyl-C (O) NH- (e.g. C) 1-3 alkyl-C (O) NH-, e.g. CH 3 -C(O)NH-、CH 3 CH 2 -C (O) NH-, or CH 3 CH 2 CH 2 -C (O) NH-), and any combination thereof, or L 1 represents-C (R) L1 R L2 ) -, wherein R is L1 、R L2 Together with the carbon atoms to which they are attached form an optionally substituted C 3- 8 Cycloalkylene radicals (e.g. optionally substituted C 3-7 Cycloalkylene group); and/or
(b1)X 1 Represents optionally substituted C 3-20 Cycloalkylene, optionally substituted 4-to 20-membered heterocyclylene, or optionally substituted 5-to 20-membered heteroarylene, wherein said C 3-20 The cycloalkylene group and the 4-to 20-membered heterocyclylene group are each independently optionally substituted with one or more (e.g., 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2, or 1) C selected from D, optionally deuterated 1-4 Alkyl (e.g. optionally deuterated C 1-3 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl), hydroxy, amino, mercapto, halogen (e.g., fluorine, chlorine, bromine, or iodine), cyano, oxo, C 1-4 Alkoxy (e.g. C 1-3 Alkoxy, e.g. methoxy, ethoxy, or propoxy), C 1-4 alkyl-NH- (e.g. C) 1-3 alkyl-NH-, e.g. CH 3 NH-、CH 3 CH 2 NH-or CH 3 CH 2 CH 2 NH-), halogenated C 1-4 Alkyl (e.g. halogenated C) 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)、NH 2 -C 1-4 Alkylene (e.g. NH 2 -C 1-3 Alkylene-, e.g. NH 2 CH 2 -、NH 2 CH 2 CH 2 -or NH 2 CH 2 CH 2 CH 2 -)、C 1-4 alkyl-NHC (O) - (e.g. C) 1-3 alkyl-NHC (O) -, e.g. CH 3 -NHC(O)-、CH 3 CH 2 NHC (O) -, or CH 3 CH 2 CH 2 -NHC(O)-)、C 1-4 alkyl-C (O) NH- (e.g. C) 1-3 alkyl-C (O) NH-, e.g. CH 3 -C(O)NH-、CH 3 CH 2 -C (O) NH-, or CH 3 CH 2 CH 2 -C (O) NH-), and any combination thereof, optionally substituted with one or more (e.g., 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2, or 1) C selected from D, optionally deuterated 1-4 Alkyl (e.g. optionally deuterated C 1-3 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl), hydroxy, amino, mercapto, halogen (e.g., fluorine, chlorine, bromine, or iodine), cyano, C 1-4 Alkoxy (e.g. C 1-3 Alkoxy, e.g. methoxy, ethoxy, or propoxy), C 1-4 alkyl-NH- (e.g. C) 1-3 alkyl-NH-, e.g. CH 3 NH-、CH 3 CH 2 NH-or CH 3 CH 2 CH 2 NH-), halogenated C 1-4 Alkyl (e.g. halogenated C) 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)、NH 2 -C 1-4 Alkylene- (e.g. NH) 2 -C 1-3 Alkylene-, e.g. NH 2 CH 2 -、NH 2 CH 2 CH 2 -or NH 2 CH 2 CH 2 CH 2 -)、C 1-4 alkyl-NHC (O) - (e.g. C) 1-3 alkyl-NHC (O) -, e.g. CH 3 -NHC(O)-、CH 3 CH 2 NHC (O) -, or CH 3 CH 2 CH 2 -NHC(O)-)、C 1-4 alkyl-C (O) NH- (e.g. C) 1-3 alkyl-C (O) NH-, e.g. CH 3 -C(O)NH-、CH 3 CH 2 -C (O) NH-, or CH 3 CH 2 CH 2 -C (O) NH-), and any combination thereof.
In some embodiments of the disclosure, (a 2) L 1 Represents C (O), vinylidene (i.e., -CH=CH-), optionally substituted C 1-5 Alkylene (e.g. optionally substituted-CH 2 -、-(CH 2 ) 2 -, a part of and- (CH) 2 ) 3 -, e.g. -CH (OH) -, -CH 2 -、-(CH 2 ) 2 -、-(CH 2 ) 3 -、-CHF 2 -and-CH 2 F-), NH, -CH=, or optionally substituted C 6-10 arylene-C 1-3 Alkylene- (e.g. optionally substituted phenylene-C 1-3 Alkylene-or optionally substituted naphthylene-C 1-3 Alkylene radicals, e.g. optionally substituted phenylene-CH 2 A method for producing a composite material X-ray a) of the above-mentioned components, wherein the symbols represent the groups X 1 Wherein said C 1-5 Alkylene and C 6-10 arylene-C 1-3 Alkylene groups are each independently optionally substituted with 1 to 4 (e.g., 1 to 3 or 1 to 2, or 1) C's selected from D, optionally deuterated 1-4 Alkyl (e.g. optionally deuterated C 1-3 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl), hydroxy, amino, mercapto, halogen (e.g., fluorine, chlorine, bromine, or iodine), cyano, C 1-4 Alkoxy (e.g. C 1-3 Alkoxy, e.g. methoxy, ethoxy, or propoxy), C 1-4 alkyl-NH- (e.g. C) 1-3 alkyl-NH-, e.g. CH 3 NH-、CH 3 CH 2 NH-or CH 3 CH 2 CH 2 NH-), halogenated C 1-4 Alkyl (e.g. halogenated C) 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)、NH 2 -C 1-4 Alkylene- (e.g. NH) 2 -C 1-3 Alkylene-, e.g. NH 2 CH 2 -、NH 2 CH 2 CH 2 -or NH 2 CH 2 CH 2 CH 2 -)、C 1-4 alkyl-NHC (O) - (e.g. C) 1-3 alkyl-NHC (O) -, e.g. CH 3 -NHC(O)-、CH 3 CH 2 NHC (O) -, or CH 3 CH 2 CH 2 -NHC(O)-)、C 1-4 alkyl-C (O) NH- (e.g. C) 1-3 alkyl-C (O) NH-, e.g. CH 3 -C(O)NH-、CH 3 CH 2 -C (O) NH-, or CH 3 CH 2 CH 2 -C (O) NH-), and any combination thereof, or L 1 represents-C (R) L1 R L2 ) -, wherein R is L1 、R L2 Together with the carbon atoms to which they are attached form an optionally substituted C 3- 8 Cycloalkyl (e.g., optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted cyclohexyl, and optionally substituted cycloheptylene); and/or
(b2)X 1 Represents optionally substituted C 3-20 Cycloalkylene, optionally substituted 4-to 20-membered heterocyclylene, or optionally substituted 5-to 20-membered heteroarylene, wherein said C 3-20 The cycloalkylene group and the 4-to 20-membered heterocyclylene group are each independently optionally substituted with one or more (e.g., 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2, or 1) C selected from D, optionally deuterated 1-4 Alkyl (e.g. optionally deuterated C 1-3 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl), hydroxy, amino, mercapto, halogen (e.g., fluorine, chlorine, bromine, or iodine), cyano, oxo, C 1-4 Alkoxy (e.g. C 1-3 Alkoxy, e.g. methoxy, ethoxy, or propoxy), C 1-4 alkyl-NH- (e.g. C) 1-3 alkyl-NH-, e.g. CH 3 NH-、CH 3 CH 2 NH-or CH 3 CH 2 CH 2 NH-), halogenated C 1-4 Alkyl (e.g. halogenated C) 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)、NH 2 -C 1-4 Alkylene (e.g. NH 2 -C 1-3 Alkylene-, e.g. NH 2 CH 2 -、NH 2 CH 2 CH 2 -or NH 2 CH 2 CH 2 CH 2 -)、C 1-4 alkyl-NHC (O) - (e.g. C) 1-3 alkyl-NHC (O) -, e.g. CH 3 -NHC(O)-、CH 3 CH 2 NHC (O) -, or CH 3 CH 2 CH 2 -NHC(O)-)、C 1-4 alkyl-C (O) NH- (e.g. C) 1-3 alkyl-C (O) NH-, e.g. CH 3 -C(O)NH-、CH 3 CH 2 -C (O) NH-, or CH 3 CH 2 CH 2 -C (O) NH-), and any combination thereof, optionally substituted with one or more (e.g., 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2, or 1) C selected from D, optionally deuterated 1-4 Alkyl (e.g. optionally deuterated C 1-3 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl), hydroxy, amino, mercapto, halogen (e.g., fluorine, chlorine, bromine, or iodine), cyano, C 1-4 Alkoxy (e.g. C 1-3 Alkoxy, e.g. methoxy, ethoxy, or propoxy), C 1-4 alkyl-NH- (e.g. C) 1-3 alkyl-NH-, e.g. CH 3 NH-、CH 3 CH 2 NH-or CH 3 CH 2 CH 2 NH-), halogenated C 1-4 Alkyl (e.g. halogenated C) 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)、NH 2 -C 1-4 Alkylene- (e.g. NH) 2 -C 1-3 Alkylene-, e.g. NH 2 CH 2 -、NH 2 CH 2 CH 2 -or NH 2 CH 2 CH 2 CH 2 -)、C 1-4 alkyl-NHC (O) - (e.g. C) 1-3 alkyl-NHC (O) -, e.g. CH 3 -NHC(O)-、CH 3 CH 2 NHC (O) -, or CH 3 CH 2 CH 2 -NHC(O)-)、C 1-4 alkyl-C (O) NH- (e.g. C) 1-3 alkyl-C (O) NH-, e.g. CH 3 -C(O)NH-、CH 3 CH 2 -C (O) NH-, or CH 3 CH 2 CH 2 -C (O) NH-), and any combination thereof.
In embodiments of the present disclosure, the number of substituents is in principle not limited by any restrictions or is automatically limited by the size of the building block.
In some embodiments of the disclosure, (a 3) L 1 Represents C (O), vinylidene, optionally substituted C 1-5 Alkylene (e.g. optionally substituted C 1-4 Alkylene or optionally substituted C 1-3 Alkylene groups, e.g. -CH (OH) -, -CH 2 -、-(CH 2 ) 2 -、-(CH 2 ) 3 -、-CHF 2 -and-CH 2 F-, -ch=, optionally substituted phenylene-C 1-5 Alkylene- (e.g. optionally substituted phenylene-C 1-3 Alkylene radicals, e.g. optionally substituted phenylene-CH 2 Optionally substituted naphthylene-C 1-5 Alkylene- (e.g. optionally substituted naphthylene-C 1-3 Alkylene-), or N (R) c1 ) Wherein R is c1 Represents H or C 1-3 Alkyl (e.g. methyl, ethyl, or propyl), the symbol X represents a group X 1 Wherein said C 1-5 Alkylene, the phenylene-C 1-5 Alkylene and said naphthylene-C 1-5 Alkylene groups are each independently optionally substituted with 1 to 10 (e.g., 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2, or 1) groups selected from D, optionally deuterated C 1-4 Alkyl, hydroxy, amino, mercapto, halogen, cyano, C 1-4 Alkoxy, C 1-4 alkyl-NH-, halo-C 1-4 Alkyl, NH 2 -C 1-4 Alkylene-, C 1-4 alkyl-NHC (O) -, C 1-4 alkyl-C (O) NH-, and substituents of any combination thereof, or L 1 represents-C (R) L1 R L2 ) -, wherein R is L1 、R L2 Together with the carbon atoms to which they are attached form an optionally substituted C 3-8 Cycloalkylene (e.g., optionally substituted cyclopropylene, optionally substituted cyclobutylene, optionally substituted cyclopentylene, optionally substituted cyclohexylene and optionally substituted cycloheptylene), and/or
(b3)X 1 Represents the following divalent groups:
cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cyclohexenylene, cycloheptylene, cyclooctylene, decahydronaphthalenyl, octahydropentalene, octahydro-1H-indenylene, spiro [3.3 ]]Heptanylene, spiro [2.5 ]]Octane subunit, spiro [3.5 ]]Nonane subunit, spiro [4.4]Nonane subunit, spiro [4.5]Decane subunit, spiro [5.5 ]]Undecylenic, p-menthylenic, m-menthylenic, quinuclidinyl, adamantylene, noradamantylene, bornylene, bicyclo [2.2.1]Heptane subunit, 2-oxo-bicyclo [2.2.1 ]]Heptane subunit or bicyclo [2.2.1]Heptene subunits optionally substituted with one or more (e.g. 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1-2, or 1) C selected from D, optionally deuterated 1-4 Alkyl, hydroxy, amino, mercapto, halogen, cyano, oxo, C 1-4 Alkoxy, C 1-4 alkyl-NH-, halo-C 1-4 Alkyl, NH 2 -C 1-4 Alkylene-, C 1-4 alkyl-NHC (O) -, C 1-4 alkyl-C (O) NH-, and any combination thereof; or (b)
Azacyclobutyl, pyrrolidinylene, imidazolidinylene, pyrazolidinylene, oxazolidinylene, thiazolidinylene, piperidinyl, piperazinylene, morpholinylene, thiomorpholinylene, azetidinylene, diazepanylene, 3-azabicyclo [3.1.0]Hexane subunit, 3-azabicyclo [3.1.1]Heptanylene, 2-azabicyclo [2.2.1]Heptanylene, 6-azabicyclo [3.1.1]Heptane subunit, 2-azabicyclo [2.2.2 ]]Octane subunit, 2, 5-diazabicyclo [2.2.1]Heptane subunit, 3, 6-diazabicyclo [3.1.1 ]]Heptanylene, 3-azabicyclo [3.2.1]Octane subunit, 3, 8-diazabicyclo [3.2.1]Octane subunit, 2, 5-diazabicyclo [2.2.2]Octane subunit, 2, 6-diazaspiro [3.3 ]]Heptanylene, 2, 7-diazaspiro [3 ].5]Nonane subunit, 3-azaspiro [5.5 ]]Undecylenic subunit, 7-azaspiro [3.5 ]]Nonane subunit, or octahydropyrrolo [3,4-c ] ]A pyrrole subunit optionally substituted with one or more (e.g. 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1-2, or 1) C selected from D, optionally deuterated 1-4 Alkyl, hydroxy, amino, mercapto, halogen, cyano, oxo, C 1-4 Alkoxy, C 1-4 alkyl-NH-, halo-C 1-4 Alkyl, NH 2 -C 1-4 Alkylene-, C 1-4 alkyl-NHC (O) -, C 1-4 alkyl-C (O) NH-, and any combination thereof; or (b)
Furanylene, oxazolylene, isoxazolylene, oxadiazolylene, thiophenylene, thiazolylene, isothiazolylene, thiadiazolylene, pyrrolylene, imidazolylene, pyrazolylene, triazolylene, pyridylene, pyrimidinylene, pyridazinylene, pyrazinylene, indolylene, isoindolylene, benzofuranylene, isobenzofuranylene, benzothiophenylene, indazoylene, benzimidazolylene, benzoxazolylene, benzisoxazolylene, benzothiazolylene, benzisothiazolylene, benzotriazole, benzo [2,1,3 ]]Oxadiazolyl and benzo [2,1,3 ] phenylene]Thiadiazolyl, benzo [1,2,3 ] phenylene]Thiadiazolyl, quinolinylene, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrazolo [1,5-a ] ]Pyridine subunit, pyrazolo [1,5-a ]]Pyrimidine subunit, imidazo [1,2-a]Pyridine subunit, 1H-pyrrolo [3,2-b]Pyridine subunit, 1H-pyrrolo [2,3-b]Pyridine subunit, 4H-fluoro [3,2-b ]]Pyrrolo [2,1-b ] pyrroles]Thiazolylene or imidazo [2,1-b]Thiazole subunits optionally substituted with one or more (e.g. 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1-2, or 1) C selected from D, optionally deuterated 1-4 Alkyl, hydroxy, amino, mercapto, halogen, cyano, C 1-4 Alkoxy, C 1-4 alkyl-NH-, halo-C 1-4 Alkyl, NH 2 -C 1-4 Alkylene-, C 1-4 alkyl-NHC (O) -, C 1-4 alkyl-C (O) NH-, and any combination thereof.
In the present disclosureIn some embodiments of (a 4) L 1 The following groups are represented:
C(O)、-CH 2 -、-(CH 2 ) 2 -、-(CH 2 ) 3 -、-CH(OH)-、-CHF 2 -、-CH 2 f-, NH, -ch=ch-, -ch=, or optionally substituted phenylene-CH 2 Wherein the symbols represent the groups X 1 Wherein the phenylene group is optionally substituted with 1-4 (e.g., 1-3 or 1-2, or 1) C selected from D, optionally deuterated 1-4 Alkyl, hydroxy, amino, mercapto, halogen, cyano, C 1-4 Alkoxy, C 1-4 alkyl-NH-, halo-C 1-4 Alkyl, NH 2 -C 1-4 Alkylene-, C 1-4 alkyl-NHC (O) -, C 1-4 alkyl-C (O) NH-, and substituents of any combination thereof, or L 1 represents-C (R) L1 R L2 ) -, wherein R is L1 、R L2 Forms, together with the carbon atoms to which they are attached, a cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene or cycloheptylene group, each of which independently is optionally substituted with one or more (e.g., 1-10, 1-8, 1-6, 1-4, 1-3, 1-2 or 1) C(s) selected from D, optionally deuterated 1-4 Alkyl, hydroxy, amino, mercapto, halogen, cyano, oxo, C 1-4 Alkoxy, C 1-4 alkyl-NH-, halo-C 1-4 Alkyl, NH 2 -C 1-4 Alkylene-, C 1-4 alkyl-NHC (O) -, C 1-4 alkyl-C (O) NH-, and any combination thereof.
In some embodiments of the disclosure, (b 4) X 1 Represents the following divalent groups:
wherein the symbol # represents a group L 1 Is connected to the connecting point of (c).
In some embodiments of the present disclosureIn the scheme, (c) L 1 Represents a bond, and X 1 Represents an optionally substituted nitrogen-containing bridged heterocyclyl (e.g., an optionally substituted 5-to 20-membered nitrogen-containing bridged heterocyclyl or an optionally substituted 5-to 15-membered nitrogen-containing bridged heterocyclyl).
In some embodiments of the disclosure, (c 1) L 1 Represents a bond, and X 1 Represents an optionally substituted 5-to 20-membered nitrogen containing bridged heterocyclyl, wherein the 5-to 20-membered nitrogen containing bridged heterocyclyl is optionally substituted with one or more (e.g. 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1-2, or 1) C selected from D, optionally deuterated 1-4 Alkyl (e.g. optionally deuterated C 1-3 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl), hydroxy, amino, mercapto, halogen (e.g., fluorine, chlorine, bromine, or iodine), cyano, oxo, C 1-4 Alkoxy (e.g. C 1-3 Alkoxy, e.g. methoxy, ethoxy, or propoxy), C 1-4 alkyl-NH- (e.g. C) 1-3 alkyl-NH-, e.g. CH 3 NH-、CH 3 CH 2 NH-or CH 3 CH 2 CH 2 NH-), halogenated C 1-4 Alkyl (e.g. halogenated C) 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)、NH 2 -C 1-4 Alkylene- (e.g. NH) 2 -C 1-3 Alkylene-, e.g. NH 2 CH 2 -、NH 2 CH 2 CH 2 -or NH 2 CH 2 CH 2 CH 2 -)、C 1-4 alkyl-NHC (O) - (e.g. C) 1-3 alkyl-NHC (O) -, e.g. CH 3 -NHC(O)-、CH 3 CH 2 NHC (O) -, or CH 3 CH 2 CH 2 -NHC(O)-)、C 1-4 alkyl-C (O) NH- (e.g. C) 1-3 alkyl-C (O) NH-, e.g. CH 3 -C(O)NH-、CH 3 CH 2 -C (O) NH-, or CH 3 CH 2 CH 2 -C (O) NH-), andsubstituted with any combination thereof.
In some embodiments of the disclosure, (c 2) L 1 Represents a bond, and X 1 Represents the following divalent groups:
3-azabicyclo [3.1.0]Hexane subunit, 3-azabicyclo [3.1.1]Heptanylene, 2-azabicyclo [2.2.1]Heptanylene, 6-azabicyclo [3.1.1]Heptane subunit, 2-azabicyclo [2.2.2 ]]Octane subunit, 2, 5-diazabicyclo [2.2.1]Heptane subunit, 3, 6-diazabicyclo [3.1.1 ]]Heptanylene, 3-azabicyclo [3.2.1]Octane subunit, 3, 8-diazabicyclo [3.2.1 ]Octane subunit, or 2, 5-diazabicyclo [2.2.2]An octane subunit wherein the divalent group is optionally substituted with one or more (e.g. 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1-2, or 1) C selected from D, optionally deuterated 1-4 Alkyl, hydroxy, amino, mercapto, halogen, cyano, oxo, C 1-4 Alkoxy, C 1-4 alkyl-NH-, halo-C 1-4 Alkyl, NH 2 -C 1-4 Alkylene-, C 1-4 alkyl-NHC (O) -, C 1-4 alkyl-C (O) NH-, and any combination thereof.
In some embodiments of the disclosure, (c 3) L 1 Represents a bond, and X 1 Represents the following divalent groups:
wherein the symbol # represents a group L 1 Is connected to the connecting point of (c).
In some embodiments of the disclosure, X 2 Representing a bond, when X 2 When representing a bond, L 1 Not a key.
In some embodiments of the disclosure, X 2 The following groups are represented:
c (O), optionally substituted C 1-5 Alkylene (e.g. optionally substituted C 1-4 Alkylene or optionally substituted C 1-3 Alkylene), optionally substituted C 3-8 Cycloalkylene, optionally substituted C 1-2 alkylene-N (R) c2 )-、-N(R c2 ) -optionally substituted C 1-2 Alkylene, or N (R) c3 ) Wherein R is c2 And R is c3 Each independently represents H or C 1-3 Alkyl (e.g., methyl, ethyl, or propyl),
wherein said C 1-5 Alkylene and said C 3-8 Cycloalkylene radicals are each independently optionally substituted with 1 to 10 (e.g., 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2, or 1) radicals selected from D, optionally deuterated C 1-4 Alkyl (e.g. optionally deuterated C 1-3 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl), hydroxy, amino, mercapto, halogen (e.g., fluorine, chlorine, bromine, or iodine), cyano, oxo, C 1-4 Alkoxy (e.g. C 1-3 Alkoxy, e.g. methoxy, ethoxy, or propoxy), C 3-8 Cycloalkyl (e.g. C 3-7 Cycloalkyl, C 3-6 Cycloalkyl or C 3-5 Cycloalkyl group, C 1-4 alkyl-NH- (e.g. C) 1-3 alkyl-NH-, e.g. CH 3 NH-、CH 3 CH 2 NH-or CH 3 CH 2 CH 2 NH-), halogenated C 1-4 Alkyl (e.g. halogenated C) 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)、NH 2 -C 1-4 Alkylene (e.g. NH 2 -C 1-3 Alkylene-, e.g. NH 2 CH 2 -、NH 2 CH 2 CH 2 -or NH 2 CH 2 CH 2 CH 2 -)、C 1-4 alkyl-NHC (O) - (e.g. C) 1-3 alkyl-NHC (O) -, e.g. CH 3 -NHC(O)-、CH 3 CH 2 NHC (O) -, or CH 3 CH 2 CH 2 -NHC(O)-)、C 1-4 alkyl-C (O) NH- (e.g. C) 1-3 alkyl-C (O) NH-, e.g. CH 3 -C(O)NH-、CH 3 CH 2 -C (O) NH-, or CH 3 CH 2 CH 2 -C (O) NH-), and any combination thereof, and
the C is 1-2 Alkylene is optionally substituted with 1 to 4 (e.g. 1 to 3 or 1 to 2, or 1) C selected from D, optionally deuterated 1-4 Alkyl (e.g. optionally deuterated C 1-3 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl), hydroxy, amino, mercapto, halogen (e.g., fluorine, chlorine, bromine, or iodine), cyano, oxo, C 1-4 Alkoxy (e.g. C 1-3 Alkoxy, e.g. methoxy, ethoxy, or propoxy), C 3-8 Cycloalkyl (e.g. C 3-7 Cycloalkyl, C 3-6 Cycloalkyl or C 3-5 Cycloalkyl group, C 1-4 alkyl-NH- (e.g. C) 1-3 alkyl-NH-, e.g. CH 3 NH-、CH 3 CH 2 NH-or CH 3 CH 2 CH 2 NH-), halogenated C 1-4 Alkyl (e.g. halogenated C) 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)、NH 2 -C 1-4 Alkylene (e.g. NH 2 -C 1-3 Alkylene-, e.g. NH 2 CH 2 -、NH 2 CH 2 CH 2 -or NH 2 CH 2 CH 2 CH 2 -)、C 1-4 alkyl-NHC (O) - (e.g. C) 1-3 alkyl-NHC (O) -, e.g. CH 3 -NHC(O)-、CH 3 CH 2 NHC (O) -, or CH 3 CH 2 CH 2 -NHC(O)-)、C 1-4 alkyl-C (O) NH- (e.g. C) 1-3 alkyl-C (O) NH-, e.g. CH 3 -C(O)NH-、CH 3 CH 2 -C (O) NH-, or CH 3 CH 2 CH 2 -C (O) NH-), and any combination thereof.
In some embodiments of the disclosure, X 2 Represents C (O) -CH 2 -、-(CH 2 ) 2 -、-(CH 2 ) 3 -, 1-cyclopropylene, NH, -CH 2 -NH-、-(CH 2 ) 2 -NH-、-NH-(CH 2 ) 2 -, or-NH-CH 2 -。
In some embodiments of the disclosure, R a1 The following structure is shown:
wherein the method comprises the steps of
Ring A represents a heterocyclylene group (e.g., a 4-to 20-membered heterocyclylene group, or a 4-to 15-membered heterocyclylene group), a cycloalkylene group (e.g., C 3-20 Cycloalkylene or C 3-15 Cycloalkylene), arylene (e.g. C 6-20 Arylene group, or C 6-10 Arylene), or heteroarylene (e.g., 5-to 20-membered heteroarylene, or 5-to 15-membered heteroarylene),
(R d1 ) m1 represents ring A optionally substituted by m1 radicals R d1 Substituted, m1 represents an integer of 0 to 10 (e.g., 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2, or 1), each R d1 Independently represents deuterium, hydroxy, amino, mercapto, halogen (e.g. fluoro, chloro, bromo or iodo), cyano, oxo, optionally deuterated C 1-6 Alkyl (e.g. optionally deuterated C 1-4 Alkyl, or optionally deuterated C 1-3 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl), optionally deuterated C 3-6 Cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), optionally deuterated C 1-6 Alkoxy (e.g. optionally deuterated C 1-5 Alkoxy, or optionally deuterated C 1-3 Alkoxy, e.g. methoxy, ethoxy, or propoxy), halo C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)、C 1-4 alkyl-NH- (e.g. C) 1-3 alkyl-NH-, e.g. CH 3 NH-、CH 3 CH 2 NH-or CH 3 CH 2 CH 2 NH-)、C 1-4 alkyl-NHC (O) - (e.g. C) 1-3 alkyl-NHC (O) -, e.g. CH 3 -NHC(O)-、CH 3 CH 2 NHC (O) -, or CH 3 CH 2 CH 2 -NHC(O)-)、C 1-4 alkyl-C (O) NH- (e.g. C) 1-3 alkyl-C (O) NH-, e.g. CH 3 -C(O)NH-、CH 3 CH 2 -C (O) NH-, or CH 3 CH 2 CH 2 -C (O) NH-), or NH 2 -C 1-6 Alkylene- (e.g. NH) 2 -C 1-4 Alkylene-or NH 2 -C 1-3 Alkylene-, e.g. NH 2 CH 2 -、NH 2 CH 2 CH 2 -or NH 2 CH 2 CH 2 CH 2 (-) -; and
ring B represents aryl (e.g. C 6-20 Aryl or C 6-10 Aryl), cycloalkyl (e.g. C 3-20 Cycloalkyl or C 3-15 Cycloalkyl), heterocyclyl (e.g., 4-to 20-membered heterocyclyl or 4-to 15-membered heterocyclyl), or heteroaryl (e.g., 5-to 20-membered heteroaryl or 5-to 15-membered heteroaryl),
(R d2 ) m2 Represents ring B optionally substituted by m2 radicals R d2 Substituted, m2 represents an integer of 0 to 10 (e.g., 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2, or 1), each R d2 Independently represents deuterium, hydroxy, amino, mercapto, halogen (e.g. fluoro, chloro, bromo or iodo), cyano, oxo, optionally deuterated C 1-6 Alkyl (e.g. optionally deuterated C 1-4 Alkyl, or optionally deuterated C 1-3 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl), optionally deuterated C 3-6 Cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), optionally deuterated C 1-6 Alkoxy (e.g. optionally deuterated C 1-5 Alkoxy, or optionally deuterated C 1-3 Alkoxy, e.g. methoxy, ethoxy, or propoxy), halo C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)、C 1-4 alkyl-NH- (e.g. C) 1-3 alkyl-NH-, e.g. CH 3 NH-、CH 3 CH 2 NH-or CH 3 CH 2 CH 2 NH-)、C 1-4 alkyl-NHC (O) - (e.g. C) 1-3 alkyl-NHC (O) -, e.g. CH 3 -NHC(O)-、CH 3 CH 2 NHC (O) -, or CH 3 CH 2 CH 2 -NHC(O)-)、C 1-4 alkyl-C (O) NH- (e.g. C) 1-3 alkyl-C (O) NH-, e.g. CH 3 -C(O)NH-、CH 3 CH 2 -C (O) NH-, or CH 3 CH 2 CH 2 -C (O) NH-), or NH 2 -C 1-6 Alkylene- (e.g. NH) 2 -C 1-4 Alkylene-or NH 2 -C 1-3 Alkylene-, e.g. NH 2 CH 2 -、NH 2 CH 2 CH 2 -or NH 2 CH 2 CH 2 CH 2 -)。
In some embodiments of the disclosure, R a1 The following structure is shown:
wherein the method comprises the steps of
Ring A represents a 4-to 20-membered heterocyclylene group, C 3-20 Cycloalkylene, C 6-20 Arylene, or 5-to 20-membered heteroarylene, (R) d1 ) m1 Represents ring A optionally substituted by m1 radicals R d1 Substituted, m1 represents an integer of 0 to 10 (e.g., 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2, or 1), each R d1 Independently represents deuterium, hydroxy, amino, mercapto, halogen, cyano, oxo, optionally deuterated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, halo C 1-6 Alkyl, C 1-4 alkyl-NH-, C 1-4 alkyl-NHC (O) -, C 1-4 alkyl-C (O) NH-, or NH 2 -C 1-6 An alkylene group; and/or
Ring B represents C 6-20 Aryl, C 3-20 Cycloalkyl, 4-to 20-membered heterocyclyl, or 5-to 20-membered heteroaryl, (R) d2 ) m2 Represents ring B optionally substituted by m2 radicals R d2 Substituted, m2 represents an integer of 0 to 10 (e.g., 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2, or 1), each R d2 Independently represents deuterium, hydroxy, amino, mercapto, halogen, cyano, oxo, optionally deuterated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, halo C 1-6 Alkyl, C 1-4 alkyl-NH-, C 1-4 alkyl-NHC (O) -, C 1-4 alkyl-C (O) NH-, or NH 2 -C 1-6 Alkylene-.
In some embodiments of the present disclosure, ring a represents the following divalent group:
Cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cyclohexenylene, cycloheptylene, cyclooctylene, decahydronaphthalenyl, octahydropentalene, octahydro-1H-indenylene, spiro [3.3 ]]Heptanylene, spiro [2.5 ]]Octane subunit, spiro [3.5 ]]Nonane subunit, spiro [4.4]Nonane subunit, spiro [4.5]Decane subunit, spiro [5.5 ]]Undecylenic, p-menthylenic, m-menthylenic, quinuclidinyl, adamantylene, noradamantylene, bornylene, bicyclo [2.2.1]Heptane subunit, 2-oxo-bicyclo [2.2.1 ]]Heptane subunit or bicyclo [2.2.1]Heptene subunits optionally substituted with one or more (e.g. 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1-2, or 1) C selected from D, hydroxy, amino, mercapto, halogen, cyano, oxo, optionally deuterated 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, halo C 1-6 Alkyl, C 1-4 alkyl-NH-, C 1-4 alkyl-NHC (O) -, C 1-4 alkyl-C (O) NH-, NH 2 -C 1-6 Alkylene-, and substituents of any combination thereof;
phenylene or naphthylene, optionally substituted with one or more (e.g., 1-6, 1-5, 1-4, 1-3, or 1-2, or 1) C selected from D, hydroxy, amino, mercapto, halogen, cyano, optionally deuterated 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, halo C 1-6 Alkyl, C 1-4 alkyl-NH-, C 1-4 alkyl-NHC (O) -, C 1-4 alkyl-C (O) NH-, NH 2 -C 1-6 Alkylene-, and substituents of any combination thereof;
azacyclobutyl, pyrrolidinylene, imidazolidinylene, pyrazolidinylene, oxazolidinylene, thiazolidinylene, piperidinyl, piperazinylene, morpholinylene, thiomorpholinylene, azetidinylene, diazepanylene, 3-azabicyclo [3.1.0]Hexane subunit, 3-azabicyclo [3.1.1]Heptanylene, 2-azabicyclo [2.2.1]Heptanylene, 6-azabicyclo [3.1.1]Heptane subunit, 2-azabicyclo [2.2.2 ]]Octane subunit, 2, 5-diazabicyclo [2.2.1]Heptane subunit, 3, 6-diazabicyclo [3.1.1 ]]Heptanylene, 3-azabicyclo [3.2.1]Octane subunit, 3, 8-diazabicyclo [3.2.1]Octane subunit, 2, 5-diazabicyclo [2.2.2]Octane subunit, 2, 6-diazaspiro [3.3 ]]Heptanylene, 2, 7-diazaspiro [3.5 ]]Nonane subunit, 3-azaspiro [5.5 ]]Undecylenic subunit, 7-azaspiro [3.5 ]]Nonane subunit or octahydropyrrolo [3,4-c ]]A pyrrole subunit optionally substituted with one or more (e.g. 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1-2, or 1) C selected from D, hydroxy, amino, mercapto, halogen, cyano, oxo, optionally deuterated 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, halo C 1-6 Alkyl, C 1-4 alkyl-NH-, C 1-4 alkyl-NHC (O) -, C 1-4 alkyl-C (O) NH-, NH 2 -C 1-6 Alkylene-, and substituents of any combination thereof; or (b)
Furanylene, oxazolylene, isoxazolylene, oxadiazolylene, thiophenylene, thiazolylene, isothiazolylene, thiadiazolylene, and picolinic acidPyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, benzo [2,1,3 ]]Oxadiazolyl and benzo [2,1,3 ] phenylene]Thiadiazolyl, benzo [1,2,3 ] phenylene]Thiadiazolyl, quinolinylene, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrazolo [1,5-a ]]Pyridine subunit, pyrazolo [1,5-a ]]Pyrimidine subunit, imidazo [1,2-a]Pyridine subunit, 1H-pyrrolo [3,2-b]Pyridine subunit, 1H-pyrrolo [2,3-b ]Pyridine subunit, 4H-fluoro [3,2-b ]]Pyrrolo [2,1-b ] pyrroles]Thiazolylene or imidazo [2,1-b]Thiazole subunits optionally substituted with one or more (e.g. 1-6, 1-5, 1-4, 1-3 or 1-2, or 1) C selected from D, hydroxy, amino, mercapto, halogen, cyano, optionally deuterated 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, halo C 1-6 Alkyl, C 1-4 alkyl-NH-, C 1-4 alkyl-NHC (O) -, C 1-4 alkyl-C (O) NH-, NH 2 -C 1-6 Alkylene-, and substituents of any combination thereof. In embodiments of the present disclosure, the number of substituents is in principle not limited by any restrictions or is automatically limited by the size of the building block.
In some embodiments of the present disclosure, ring B represents the following group:
cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, decalinyl, octahydropentalenyl, octahydro-1H-indenyl, spiro [3.3 ]]Heptyl, spiro [2.5 ]]Octyl, spiro [3.5 ]]Nonylalkyl, spiro [4.4 ]]Nonylalkyl, spiro [4.5 ]]Decyl and spiro [5.5 ]]Undecyl, p-menthyl, m-menthyl, quinuclidinyl, adamantyl, noradamantyl, bornyl, bicyclo [2.2.1 ]Heptyl, 2-oxo-bicyclo [2.2.1]Heptyl or bicyclo [2.2.1]Heptenyl groups optionally substituted with one or more (e.g., 1-10, 1-9, 1-8,1-7, 1-6, 1-5, 1-4, 1-3 or 1-2, or 1) C selected from D, hydroxy, amino, mercapto, halogen, cyano, oxo, optionally deuterated 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, halo C 1-6 Alkyl, C 1-4 alkyl-NH-, C 1-4 alkyl-NHC (O) -, C 1-4 alkyl-C (O) NH-, NH 2 -C 1-6 Alkylene-, and substituents of any combination thereof;
phenyl or naphthyl, optionally substituted with one or more (e.g. 1-6, 1-5, 1-4, 1-3 or 1-2, or 1) C selected from D, hydroxy, amino, mercapto, halogen, cyano, optionally deuterated 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, halo C 1-6 Alkyl, C 1-4 alkyl-NH-, C 1-4 alkyl-NHC (O) -, C 1-4 alkyl-C (O) NH-, NH 2 -C 1-6 Alkylene-, and substituents of any combination thereof;
azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, diazepinyl, 3-azabicyclo [3.1.0 ]Hexalkyl, 3-azabicyclo [3.1.1]Heptyl, 2-azabicyclo [2.2.1]Heptyl, 6-azabicyclo [3.1.1]Heptyl, 2-azabicyclo [2.2.2]Octyl, 2, 5-diazabicyclo [2.2.1]Heptyl, 3, 6-diazabicyclo [3.1.1]Heptyl, 3-azabicyclo [3.2.1]Octyl, 3, 8-diazabicyclo [3.2.1]Octyl, 2, 5-diazabicyclo [2.2.2]Octyl, 2, 6-diazaspiro [3.3 ]]Heptyl, 2, 7-diazaspiro [3.5 ]]Nonylalkyl, 3-azaspiro [5.5 ]]Undecyl, 7-azaspiro [3.5 ]]Nonylalkyl or octahydropyrrolo [3,4-c ]]Pyrrolyl optionally substituted with one or more (e.g. 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1-2, or 1) C selected from D, hydroxy, amino, mercapto, halogen, cyano, oxo, optionally deuterated 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, halo C 1-6 Alkyl, C 1-4 alkyl-NH-, C 1-4 alkyl-NHC (O) -, C 1-4 alkyl-C (O) NH-, NH 2 -C 1-6 Alkylene-, and substituents of any combination thereof; or (b)
Furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazole, benzo [2,1,3 ]Oxadiazolyl and benzo [2,1,3 ]]Thiadiazolyl and benzo [1,2,3 ]]Thiadiazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrazolo [1,5-a ]]Pyridinyl, pyrazolo [1,5-a ]]Pyrimidinyl, imidazo [1,2-a ]]Pyridyl, 1H-pyrrolo [3,2-b]Pyridyl, 1H-pyrrolo [2,3-b]Pyridyl, 4H-fluoro [3,2-b ]]Pyrrolo [2,1-b ] pyrrolyl]Thiazolyl or imidazo [2,1-b]Thiazolyl optionally substituted with one or more (e.g., 1-6, 1-5, 1-4, 1-3 or 1-2, or 1) C selected from D, hydroxy, amino, mercapto, halogen, cyano, optionally deuterated 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, halo C 1-6 Alkyl, C 1-4 alkyl-NH-, C 1-4 alkyl-NHC (O) -, C 1-4 alkyl-C (O) NH-, NH 2 -C 1-6 Alkylene-, and substituents of any combination thereof. In embodiments of the present disclosure, the number of substituents is in principle not limited by any restrictions or is automatically limited by the size of the building block.
In some embodiments of the present disclosure, ring a represents the following divalent group:
wherein the symbols represent the connection points to ring B.
In some embodiments of the present disclosure, ring B represents the following group:
In some embodiments of the disclosure, R a1 The following structure is shown:
in some embodiments of the present disclosure, the compound of formula (I) is-X 1 -X 2 -R a1 The following structure is shown:
in some embodiments of the present disclosure, the compound of formula (I) is also a compound of formula (II) or a compound of formula (III):
wherein the radicals R b1 、R b2 、R b3 、R b4 、R b5 、(R a ) n 、X、L 1 、X 1 、X 2 And R is a1 As aboveCompounds of formula (I) are defined in the various embodiments herein.
In some embodiments of the present disclosure, the compound of formula (I) is also a compound of formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (IIIa), formula (IIIb), formula (IIIc), or formula (IIId):
wherein the radicals R b1 、R b2 、R b3 、R b4 、R b5 、(R a ) n 、X、L 1 、X 1 、X 2 And R is a1 As defined above for compounds of formula (I) and embodiments thereof.
Particularly preferred are the compounds of table 1 of the present invention and salts thereof (especially pharmaceutically acceptable salts, e.g. their hydrochloride salts), enantiomers, diastereomers, solvates, polymorphs:
TABLE 1 Compounds of the invention
Other forms of the compounds (including salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs, or polymorphs of the compound)
The compounds of the present disclosure have the structure of any of formula (I), formula (II), formula (III), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (IIIa), formula (IIIb), formula (IIIc), or formula (IIId). Unless otherwise indicated, when referring to compounds of the present disclosure, reference is made to compounds including any of formula (I), formula (II), formula (III), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (IIIa), formula (IIIb), formula (IIIc), or formula (IIId), as well as specific compounds falling within the scope of these formulae.
It is to be appreciated that compounds of the present disclosure, including compounds of formula (I), formula (II), formula (III), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (IIIa), formula (IIIb), formula (IIIc), or formula (IIId), may have a stereochemical configuration and thus may exist in more than one stereoisomer. The disclosure also relates to optically enriched compounds having a steric configuration, such as greater than 90% ee, such as about 95% ee or 97% ee, or greater than 99% ee, and mixtures thereof, including racemic mixtures. As used herein, "optically enriched" means that a mixture of enantiomers consists of a significantly greater proportion of one enantiomer, and can be described by enantiomeric excess (ee%). Purification of the isomers and separation of the isomer mixtures may be accomplished by standard techniques known in the art (e.g., column chromatography, preparative TLC, preparative HPLC, asymmetric synthesis (e.g., by using chiral intermediates), chiral resolution, and/or the like).
In some embodiments, polymorphic forms of the compounds of the present disclosure or salts of the compounds of the present disclosure are also provided. Salts of the compounds of the present disclosure may be pharmaceutically acceptable salts including, but not limited to, hydrochloride, sulfate, citrate, maleate, sulfonate, citrate, lactate, tartrate, fumarate, phosphate, dihydrogen phosphate, pyrophosphate, metaphosphate, oxalate, malonate, benzoate, mandelate, succinate, trifluoroacetate, glycolate, p-toluenesulfonate, and the like. The compounds of the present disclosure can exist in a pharmaceutically acceptable solvent such as water, ethanol, and the like, in the form of non-solvates or solvates. In some embodiments, compounds of the present disclosure may be prepared as prodrugs or prodrugs. The prodrug can be converted into the parent drug in the body to act. In some embodiments, isotopically-labeled compounds of the present disclosure are also provided, examples of isotopes including deuterium (D or 2 H)。
III pharmaceutical composition/formulation
In some embodiments, the present disclosure provides a pharmaceutical composition comprising as an active ingredient a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, isotopically enriched analog, polymorph, prodrug, stereoisomer (including enantiomer), or mixture of stereoisomers thereof, and at least one pharmaceutically acceptable carrier.
In some embodiments, pharmaceutically acceptable carriers include, but are not limited to, fillers, stabilizers, dispersants, suspending agents, diluents, excipients, thickeners, colorants, solvents, or encapsulating materials. The carrier is compatible with the other ingredients of the formulation, including the compounds useful in this disclosure, and not deleterious to the patient, and must be "acceptable". Some examples of materials for pharmaceutically acceptable carriers include: sugars such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; diols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; surfactant phosphate buffer solution; polyoxyethylene, polyvinylpyrrolidone, polyacrylamide, poloxamer; and other non-toxic compatible substances used in pharmaceutical formulations.
The pharmaceutical compositions described in the present disclosure further comprise at least one second therapeutic agent, such as an anticancer agent. The second therapeutic agent may be used in combination with a compound of formula (I) as described in the present disclosure to treat a disease or disorder as described in the present disclosure. The second therapeutic agent includes, but is not limited to, a chemotherapeutic agent, an immunotherapeutic agent, a gene therapeutic agent, an anti-angiogenic agent, an immunomodulator, and the like.
Pharmaceutical compositions described herein comprising as an active ingredient a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein may be prepared in the form of suitable formulations such as spray formulations, patches, tablets (e.g. conventional tablets, dispersible tablets, orally disintegrating tablets), capsules (e.g. soft capsules, hard capsules, enteric-coated capsules), dragees, powders, granules, powder injection, suppositories, or liquid formulations (e.g. suspensions (e.g. aqueous or oily suspensions), solutions, emulsions or syrups), or conventional injectable solutions such as injectable solutions (e.g. with water, ringer's solution or isotonic sodium chloride solution, etc. as a carrier or sterile solution according to methods known in the art) according to suitable routes of administration including, but not limited to, nasal administration, inhalation, topical administration, oral mucosal administration, rectal administration, pleural cavity administration, peritoneal administration, vaginal administration, intramuscular administration, subcutaneous administration, transdermal administration, parenteral administration and intravenous administration. The person skilled in the art can also prepare the compounds of formula (I) as desired in conventional, dispersible, chewable, orally fast disintegrating or fast dissolving formulations, or in slow-release or controlled-release capsules.
The compounds of formula (I) as described in the present disclosure as active ingredients are contained in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a subject a therapeutically effective amount for the indication in need of treatment without causing serious toxic effects in the treated subject. The dosage of active compound for use in all diseases or conditions mentioned herein is, for example, from about 5ng/kg subject body weight/day to 500mg/kg subject body weight/day, from about 10ng/kg subject body weight/day to 300mg/kg subject body weight/day, for example, from 0.1 to 100mg/kg subject body weight/day, or from 0.5 to about 25mg/kg subject body weight/day.
The compounds of formula (I) or pharmaceutically acceptable salts thereof described in this disclosure may be conveniently administered in any suitable formulation format, including, but not limited to, containing less than 1mg,1mg to 3000mg,5mg to 1000mg, e.g., 5 to 500mg,25 to 250mg of active ingredient per unit dosage form.
IV kit/packaging article
A compound of formula (I), or a pharmaceutically acceptable salt, solvate, isotopically enriched analog, polymorph, prodrug, stereoisomer (including enantiomer), or mixture of stereoisomers thereof, as described herein, for use as a medicament. The pharmaceutical agents of the present disclosure or the pharmaceutical compositions of the present disclosure may be present in a kit/packaging article. The kit/packaging article may comprise a package or container. Packaging or containers include, but are not limited to, ampoules (ampoules), blister packs, pharmaceutical plastic bottles, vials, pharmaceutical glass bottles, containers, syringes, laminated flexible packages, co-extruded film infusion containers, test tubes, dispensing devices, and the like. The kit/packaging article may contain instructions for use of the product.
V, method and use
The compounds of formula (I), or pharmaceutically acceptable salts, solvates, isotopically enriched analogs, polymorphs, prodrugs, stereoisomers (including enantiomers), or mixtures of stereoisomers thereof, described herein, may also be used as medicaments. In particular, the compounds of formula (I) described herein, or pharmaceutically acceptable salts, solvates, isotopically enriched analogs, polymorphs, prodrugs, stereoisomers (including enantiomers), or mixtures of stereoisomers thereof, may be used in the manufacture of a medicament for the prevention and/or treatment of a disease or condition associated with the cereblon protein. Diseases or disorders associated with the cereblon protein include: tumors, infectious diseases, inflammatory diseases, autoimmune diseases, anemia, hemorrhagic shock, transplant rejection, multiple Organ Dysfunction Syndrome (MODS), sarcoidosis, adult respiratory distress syndrome, cardiovascular diseases, richter Syndrome (RS), acute liver failure, or diabetes. In some embodiments, the disease or disorder associated with the cereblon protein includes, but is not limited to: tumors, infectious diseases, inflammatory diseases, autoimmune diseases, anemia, hemorrhagic shock, transplant rejection, multiple Organ Dysfunction Syndrome (MODS), sarcoidosis, adult respiratory distress syndrome, cardiovascular diseases, richter Syndrome (RS), acute liver failure, or diabetes. In some embodiments, the disease or disorder associated with the cereblon protein includes, but is not limited to: myeloma, including multiple myeloma, plasma cell myeloma, smoldering multiple myeloma; myelofibrosis; bone marrow disease; myelodysplastic syndrome (MDS); myelodysplastic syndrome treated in the past; transplantation-related cancers; neutropenia; leukemia, including acute myelogenous leukemia, chronic myelogenous leukemia, B-cell chronic lymphocytic leukemia, anemia associated with leukemia, acute Myelogenous Leukemia (AML); lymphomas including diffuse large B-cell lymphomas, non-hodgkin lymphomas, anaplastic large cell lymphomas, CD20 positive lymphomas, mantle cell lymphomas, primary lymphomas, B-cell lymphomas, recurrent B-cell non-hodgkin lymphomas, recurrent diffuse large B-cell lymphomas, recurrent mediastinal (thymus) large B-cell lymphomas, primary mediastinal (thymus) large B-cell lymphomas, recurrent transformed non-hodgkin lymphomas, refractory B-cell non-hodgkin lymphomas, refractory diffuse large B-cell lymphomas, refractory primary mediastinal (thymus) large B-cell lymphomas, refractory transformed non-hodgkin lymphomas; thyroid cancer; melanoma; lung cancer, including lung adenocarcinoma and lung squamous carcinoma; inflammatory myofibroblastic tumor; colorectal cancer; intestinal cancer; glioma of brain; astrocytoma; ovarian cancer; bronchial carcinoma; prostate cancer; breast cancer, including triple negative breast cancer, sporadic breast cancer and cowden patients; pancreatic cancer; central nervous system cancer; neuroblastoma; glioma; peripheral nerve epithelial tumors; an extramedullary plasma cell tumor; plasmacytoma; stomach cancer; gastrointestinal stromal tumor; esophageal cancer; large intestine adenocarcinoma; esophageal squamous cell carcinoma; liver cancer; renal cell carcinoma; bladder cancer; endometrial cancer; uterine cancer; cancer of the head and neck; brain cancer; oral cancer; sarcomas, including rhabdomyosarcoma, various adipose-derived tumors, ewing's sarcoma/primitive neuroectodermal tumors (Ewing/PNETs), and leiomyosarcoma; urothelial cancer; basal cell carcinoma; squamous cell carcinoma of the oral cavity; bile duct cancer; bone cancer; cervical cancer; skin cancer; richter Syndrome (RS); sepsis syndrome; autoimmune diseases including rheumatoid arthritis, autoimmune encephalomyelitis, ankylosing spondylitis, psoriasis, systemic lupus erythematosus, multiple sclerosis, recurrent oral ulcer, kawasaki disease, polymyositis/dermatomyositis, sjogren's syndrome, atopic dermatitis; keratoconjunctival dryness; inflammatory diseases including crohn's disease and ulcerative colitis, pneumonia, osteoarthritis, synovitis, systemic inflammatory response syndrome, airway inflammation, bronchitis; cerebral malaria; infectious diseases including viral pneumonia, AIDS, covd-19 novel coronavirus infection, gram negative bacterial infection, gram positive bacterial infection, tuberculosis, etc.; infectious shock; tuberculosis; bacterial meningitis; chronic obstructive pulmonary disease; asthma; hemorrhagic shock; organ (including kidney, heart, lung) or tissue graft rejection; diabetes mellitus; sarcoidosis; adult respiratory distress syndrome; anemia; aplastic anemia of children; cardiovascular disease (e.g., coronary heart disease, congestive heart failure, myocardial infarction, atherosclerosis); multiple organ failure due to cachexia and septic shock; or acute liver failure.
The present disclosure provides methods for preventing and/or treating a disease or disorder associated with cereblon protein, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein as an active ingredient. In some embodiments, the disease or disorder associated with the cereblon protein comprises: tumors, infectious diseases, inflammatory diseases, autoimmune diseases, anemia, hemorrhagic shock, transplant rejection, multiple Organ Dysfunction Syndrome (MODS), sarcoidosis, adult respiratory distress syndrome, cardiovascular diseases, richter Syndrome (RS), acute liver failure, or diabetes. In some embodiments, the disease or disorder associated with the cereblon protein includes, but is not limited to: myeloma, including multiple myeloma, plasma cell myeloma, smoldering multiple myeloma; myelofibrosis; bone marrow disease; myelodysplastic syndrome (MDS); myelodysplastic syndrome treated in the past; transplantation-related cancers; neutropenia; leukemia, including acute myelogenous leukemia, chronic myelogenous leukemia, B-cell chronic lymphocytic leukemia, anemia associated with leukemia, acute Myelogenous Leukemia (AML); lymphomas including diffuse large B-cell lymphomas, non-hodgkin lymphomas, anaplastic large cell lymphomas, CD20 positive lymphomas, mantle cell lymphomas, primary lymphomas, B-cell lymphomas, recurrent B-cell non-hodgkin lymphomas, recurrent diffuse large B-cell lymphomas, recurrent mediastinal (thymus) large B-cell lymphomas, primary mediastinal (thymus) large B-cell lymphomas, recurrent transformed non-hodgkin lymphomas, refractory B-cell non-hodgkin lymphomas, refractory diffuse large B-cell lymphomas, refractory primary mediastinal (thymus) large B-cell lymphomas, refractory transformed non-hodgkin lymphomas; thyroid cancer; melanoma; lung cancer, including lung adenocarcinoma and lung squamous carcinoma; inflammatory myofibroblastic tumor; colorectal cancer; intestinal cancer; glioma of brain; astrocytoma; ovarian cancer; bronchial carcinoma; prostate cancer; breast cancer, including triple negative breast cancer, sporadic breast cancer and cowden patients; pancreatic cancer; central nervous system cancer; neuroblastoma; glioma; peripheral nerve epithelial tumors; an extramedullary plasma cell tumor; plasmacytoma; stomach cancer; gastrointestinal stromal tumor; esophageal cancer; large intestine adenocarcinoma; esophageal squamous cell carcinoma; liver cancer; renal cell carcinoma; bladder cancer; endometrial cancer; uterine cancer; cancer of the head and neck; brain cancer; oral cancer; sarcomas, including rhabdomyosarcoma, various adipose-derived tumors, ewing's sarcoma/primitive neuroectodermal tumors (Ewing/PNETs), and leiomyosarcoma; urothelial cancer; basal cell carcinoma; squamous cell carcinoma of the oral cavity; bile duct cancer; bone cancer; cervical cancer; skin cancer; richter Syndrome (RS); sepsis syndrome; autoimmune diseases including rheumatoid arthritis, autoimmune encephalomyelitis, ankylosing spondylitis, psoriasis, systemic lupus erythematosus, multiple sclerosis, recurrent oral ulcer, kawasaki disease, polymyositis/dermatomyositis, sjogren's syndrome, atopic dermatitis; keratoconjunctival dryness; inflammatory diseases including crohn's disease and ulcerative colitis, pneumonia, osteoarthritis, synovitis, systemic inflammatory response syndrome, airway inflammation, bronchitis; cerebral malaria; infectious diseases including viral pneumonia, AIDS, covd-19 novel coronavirus infection, gram negative bacterial infection, gram positive bacterial infection, tuberculosis, etc.; infectious shock; tuberculosis; bacterial meningitis; chronic obstructive pulmonary disease; asthma; hemorrhagic shock; organ (including kidney, heart, lung) or tissue graft rejection; diabetes mellitus; sarcoidosis; adult respiratory distress syndrome; anemia; aplastic anemia of children; cardiovascular disease (e.g., coronary heart disease, congestive heart failure, myocardial infarction, atherosclerosis); multiple organ failure due to cachexia and septic shock; or acute liver failure.
In a method for preventing and/or treating a disease or condition associated with cereblon protein, a therapeutically effective amount of a compound of formula (I) as described in the present disclosure, or a pharmaceutical composition comprising a compound of formula (I) as an active ingredient as described in the present disclosure, is administered to the subject by at least one administration mode selected from nasal administration, inhalation administration, topical administration, oral mucosal administration, rectal administration, pleural cavity administration, peritoneal administration, vaginal administration, intramuscular administration, subcutaneous administration, transdermal administration, epidural cavity administration, intrathecal administration and intravenous administration.
The term "treatment" or "treatment" refers to the administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as described in the present disclosure, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, as an active ingredient, to a subject to slow (alleviate) the progression of an undesired disease or disorder (e.g., tumor). Beneficial or desired clinical results of the present disclosure include, but are not limited to: alleviating symptoms, lessening the severity of the disease, stabilizing the state of the disease, delaying or slowing the progression of the disease, improving or alleviating the condition, and alleviating the disease.
The "therapeutically effective amount" of a compound of the present disclosure depends on a variety of factors including the activity of the particular compound being used, the metabolic stability and length of action of that compound, the age, sex, and weight of the patient, the general medical condition of the patient, the mode and time of administration, the rate of excretion, drug combination, and the disease or condition of the patient being treated. One skilled in the art will be able to determine the appropriate dosage based on these and other factors.
It will be appreciated that the choice of the active compound(s) and/or composition(s) and the dosage thereof will depend on the individual base case (the individual case should generally be optimized). The administration and dosing regimen should be within the ability of those skilled in the art, and the appropriate dosage will depend on many factors including the level of knowledge of the ordinarily skilled physician, veterinarian or researcher (see, e.g., lijun monograph, "clinical pharmacology", 4 th edition, human health Press (2008)).
The patient or subject treated as described above refers to an animal, such as a mammal, including but not limited to a primate (e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, guinea pig, rat, mouse, etc.
VI definition of
The following words, phrases and symbols used in the present specification have the meanings as described below in general unless otherwise indicated.
Generally, the nomenclature used herein (including IUPAC nomenclature) and the laboratory procedures described below (including those used in cell culture, organic chemistry, analytical chemistry, pharmacology, and the like) are those well known and commonly employed in the art. Unless defined otherwise, all scientific and technical terms used herein in connection with the disclosure described herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, in the claims and/or the specification, the terms "a" or "an" when used in conjunction with the term "comprising" or noun may have the meaning of "one" but are also consistent with the meaning of "one or more", "at least one", and "one or more". Similarly, the term "another" or "other" may mean at least a second or more.
It will be understood that whenever aspects are described herein by the terms "comprising" or "including," other similar aspects are provided as described by "consisting of …" and/or "consisting essentially of ….
The term "about" alone or in combination is used herein to mean approximately, about, or around …. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term "about" can modify a value above and below the stated value by changing, for example, 10%, 5%, 2%, or 1% up or down (up or down).
The term "… …, used herein, alone or in combination, means a bond" meaning that it is a bond linker (i.e., meaning that it is absent). For example, the term L 1 The expression "means L 1 Is a bond linkage. In other words, when L 1 In the case of a bond, a group X of the structure of formula (I) 1 Directly to the benzene ring in the structure of formula (I). For example, the term "X 2 The expression bond "means X 2 Is a bond linkage. In other words, when X 2 R in the structure of formula (I) is a bond a1 Directly to a group X in a compound of formula (I) 1 。
The term "optionally substituted" as used herein, alone or in combination, means that the indicated group may be unsubstituted or substituted with one or more substituents as defined herein. The term "optionally substituted with … …" is used interchangeably herein with "unsubstituted or substituted. The term "substituted" generally means that one or more hydrogens in the structure referred to are replaced with a specific substituent, either the same or different. The number of substituents is in principle not subject to any restrictions, or is automatically limited by the size of the building unit (i.e. the total number of hydrogen atoms that can be replaced of the building unit), or is as defined explicitly herein.
In this context, the bond broken by the wavy line shows the point of attachment of the depicted group to the rest of the molecule. For example, the radicals R depicted below a1
Ring A representing the group and group X 2 And (5) connection. For example, the divalent group X depicted below 1 ：The symbol # represents an atom N and a group L 1 And another atom N is attached to the radical X 2 And (5) connection. In this context, without specifying the point of attachment of the groups, e.g. X 2 Represented radical-CH 2 -NH-, either end of the group (e.g. CH 2 ) With a group X of compounds of formula (I) 1 To the other end of which is attached to the radical R a1 And (5) connection.
The term "halogen atom" or "halogen" as used herein, alone or in combination, refers to fluorine, chlorine, bromine or iodine.
The term "alkyl" as used herein, alone or in combination, refers to a straight or branched chain alkyl group. The term "C x -C y Alkyl "or" C x-y Alkyl "(x and y are each integers) refers to a straight or branched chain alkyl group containing from x to y carbon atoms. The term "C" used in the present invention alone or in combination 1 -C 6 Alkyl "refers to straight or branched chain alkyl groups containing 1 to 6 carbon atoms, examples of which include C 1 -C 5 Alkyl, C 1 -C 4 Alkyl, and C 1 -C 3 Alkyl groups, and the like. The term "C" used in the present invention alone or in combination 1 -C 4 Alkyl "refers to a straight or branched chain alkyl group containing 1 to 4 carbon atoms. The term "C 1 -C 6 Examples of alkyl "include C 1 -C 5 Alkyl, C 1 -C 4 Alkyl, C 1 -C 3 Alkyl, C 1 -C 2 Alkyl, and methyl. The term "C 1 -C 6 Representative examples of alkyl "include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, and hexyl. The term "C" used in the present invention alone or in combination 1-4 Alkyl "refers to a straight or branched chain alkyl group containing 1 to 4 carbon atoms. C of the present disclosure 1-4 Examples of alkyl groups include C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl, and methyl. The term "C 1 -C 4 Representative examples of alkyl "include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. The term "C" of the present disclosure 1-3 Alkyl "or" C 1 -C 3 Alkyl "means containingAlkyl groups having 1 to 3 carbon atoms, representative examples of which include methyl, ethyl, n-propyl and isopropyl. In the present disclosure, the "alkyl" is optionally substituted, and the substituents may be one or more selected from D (i.e., deuterium), halogen, hydroxy, cyano, C 1-3 Alkyl, C 1-3 Substituents for alkoxy, trifluoromethyl, heterocyclyl (e.g., quaternary to octamembered heterocycles), or combinations thereof.
The term "haloalkyl" as used herein, alone or in combination, refers to a straight or branched chain alkyl group substituted with one or more halogens wherein one or more hydrogens in the alkyl group are replaced with a halogen. The term "halogenated C x -C y Alkyl "or" halo C x-y Alkyl "(x and y are each integers) refers to a straight or branched chain alkyl group containing from x to y carbon atoms substituted with one or more halogens. The term "haloC" used in this disclosure, alone or in combination 1-6 Alkyl "refers to a straight or branched chain alkyl group containing 1 to 6 carbon atoms substituted with one or more halogens. Halogenated C of the present disclosure 1-6 Examples of alkyl groups include halogenated C 1-6 Alkyl, halo C 1-5 Alkyl, halo C 1-4 Alkyl, halo C 1-3 Alkyl, halo C 1-2 Alkyl, and halomethyl. The term "halogenated C 1-6 Representative examples of alkyl "include halomethyl, haloethyl, halo-n-propyl, halo-isopropyl, halo-n-butyl, halo-isobutyl, halo-sec-butyl, halo-tert-butyl, halo-pentyl, halo-isopentyl, halo-neopentyl, halo-tert-pentyl, and halo-hexyl, including, inter alia, F, for example 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -and CH 2 ClCH 2 -. The term "halo C" of the present disclosure 1-3 Alkyl "or" halo C 1 -C 3 Alkyl "means an alkyl group having 1 to 3 carbon atoms substituted with one or more halogens, representative examples of which include halomethyl, haloethyl, halo-n-propyl, and halo-isopropyl, including, inter alia, F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -and CH 2 ClCH 2 -。
The term "deuterated" as used herein, alone or in combination, means that one or more hydrogens in the group referred to are replaced with a deuterium atom (i.e., D).
The term "deuterated C" used herein, alone or in combination x -C y Alkyl "or" deuterated C x-y Alkyl "(x and y are each integers) refers to a straight or branched chain alkyl group containing from x to y carbon atoms substituted with one or more deuterium atoms. The term "deuterated C" used in this disclosure, alone or in combination 1-6 Alkyl "refers to a straight or branched chain alkyl group containing 1 to 6 carbon atoms substituted with one or more deuterium atoms. Deuterated C of the present disclosure 1-6 Examples of alkyl groups include deuterated C 1-5 Alkyl radicals, e.g. deuterated C 1-4 Alkyl, deuterated C 2-5 Alkyl, deuterated C 1-3 Alkyl, deuterated C 1-2 Alkyl, and deuterated methyl. The term "deuterated C 1-6 Representative examples of alkyl "include perdeuterated methyl (CD) 3 ) Perdeuterated ethyl (CD) 3 CD 2 ) A perdeuterated n-propyl group, a perdeuterated isopropyl group, a perdeuterated n-butyl group, a perdeuterated isobutyl group, a perdeuterated sec-butyl group, a perdeuterated tert-butyl group, a perdeuterated pentyl group, a perdeuterated isopentyl group, a perdeuterated neopentyl group, a perdeuterated tert-pentyl group, and a perdeuterated hexyl group. The term "deuterated C" of the present disclosure 1-3 Alkyl "or" deuterated C 1 -C 3 Alkyl "refers to an alkyl group containing 1 to 3 carbon atoms substituted with one or more deuterium atoms, representative examples of which include perdeuterated methyl (CD) 3 (-) and perdeuterated ethyl (CD) 3 CD 2 )。
The term "alkylene" (which is used interchangeably with "alkylene chain") as used herein, alone or in combination, refers to a straight or branched divalent saturated hydrocarbon group consisting of carbon and hydrogen. The term "C x -C y Alkylene "or" C x - y Alkylene (x and y are each integers) meansStraight or branched chain alkylene groups containing from x to y carbon atoms. The term "C" used in the present invention alone or in combination 1 -C 5 Alkylene "refers to a straight or branched chain alkylene group containing 1 to 5 carbon atoms, examples of which include C 2 -C 5 Alkylene, C 1 -C 4 Alkylene, C 1 -C 3 Alkylene, C 1 -C 2 Alkylene and methylene. Representative examples include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, tert-butylene, pentylene, isopentylene, neopentylene, and terylene. In the present disclosure, the "alkylene" is optionally substituted, the substituents may be one or more (e.g., 1-10, 1-6, 1-5, 1-4, 1-3, 2-3, or 1) C selected from D, optionally deuterated 1-4 Alkyl, C 3-6 Cycloalkyl, hydroxy, amino, mercapto, halogen, cyano, C 1 -C 4 Alkoxy, C 1 -C 4 Alkylamino, halo C 1 -C 4 Alkyl, amino C 1-4 Alkylene, C 1-4 alkyl-NHC (O) -, C 1-4 alkyl-C (O) NH-, and substituents of any combination thereof.
The term "alkoxy", as used herein, alone or in combination, refers to a straight or branched chain alkoxy group having the structural formula alkyl-O-. Alternatively, the alkyl portion of the alkoxy group may contain 1 to 10 carbon atoms. Representative examples of "alkoxy" include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, 2-pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, 2-hexyloxy, 3-methylpentyloxy, and the like. The term "C 1 -C 4 Alkoxy "or" C 1-4 Alkoxy "refers to straight or branched chain alkoxy groups containing 1 to 4 carbon atoms. C (C) 1-4 Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy.
The term "haloalkoxy" as used herein, alone or in combination, refers to an alkoxy group substituted with one or more halogens. Optionally, aThe alkyl portion of the alkoxy group may contain 1 to 10 carbon atoms. Examples of "haloalkoxy" include haloC 1-6 Alkoxy or halo C 1-4 An alkoxy group. Representative examples include, but are not limited to, F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-and CH 2 ClCH 2 -O-。
The term "alkyl-NH-" as used herein, alone or in combination, refers to a straight or branched chain alkyl-NH-, wherein alkyl is as defined above. Alternatively, the alkyl portion of the alkyl-NH-group may contain 1 to 6 carbon atoms, i.e., C 1-6 alkyl-NH-. Representative examples of "alkyl-NH-" include, but are not limited to, methyl-NH-, ethyl-NH-, propyl-NH-, isopropyl-NH-, n-butyl-NH-, isobutyl-NH-, t-butyl-NH-, pentyl-NH-, hexyl-NH-, and the like. The term "C 1 -C 4 alkyl-NH- "or" C 1-4 alkyl-NH- "means a straight or branched chain alkyl-NH-containing from 1 to 4 carbon atoms. C (C) 1-4 Representative examples of alkyl-NH-include, but are not limited to, methyl-NH-, ethyl-NH-, n-propyl-NH-, isopropyl-NH-, n-butyl-NH-, isobutyl-NH-, and tert-butyl-NH-.
The term "NH" as used herein, alone or in combination 2 -alkylene "refers to an amino-substituted straight or branched chain alkylene group, wherein alkylene is as defined above. Alternatively, "NH 2 The alkylene portion of the alkylene group "may contain 1 to 6 carbon atoms. The term "NH 2 -C 1-4 Alkylene "or" amino-C 1-4 Alkylene- "refers to an amino-substituted straight or branched chain alkylene group containing 1 to 4 carbon atoms. NH (NH) 2 -C 1-4 Representative examples of alkylene groups include, but are not limited to, NH 2 -CH 2 -、NH 2 -CH 2 CH 2 -, a part of NH and NH 2 -CH 2 CH 2 CH 2 -。
The term "alkyl-NHC (O) -" as used herein, alone or in combination, refers to a straight or branched chain alkyl-NHC (O) -, in which the alkane isThe radicals are as defined above. Alternatively, the alkyl moiety of the alkyl-NHC (O) -can contain 1-6 carbon atoms. The term "C 1 -C 4 alkyl-NHC (O) - "or" C 1-4 alkyl-NHC (O) - "refers to a straight or branched chain alkyl-NHC (O) -, containing from 1 to 4 carbon atoms. C (C) 1- 4 Representative examples of alkyl-NHC (O) -include, but are not limited to CH 3 -NHC(O)-、CH 3 CH 2 NHC (O) -, CH 3 CH 2 CH 2 -NHC(O)-。
The term "alkyl-C (O) NH-" as used herein, alone or in combination, refers to a straight or branched chain alkyl-C (O) NH-, wherein alkyl is as defined above. Alternatively, the alkyl portion of the alkyl-C (O) NH-may contain 1 to 6 carbon atoms. The term "C 1 -C 4 alkyl-C (O) NH- "or" C 1-4 alkyl-C (O) NH- "means a straight or branched chain alkyl-C (O) NH-containing from 1 to 4 carbon atoms. C (C) 1- 4 Representative examples of alkyl-C (O) NH-include, but are not limited to CH 3 -C(O)NH-、CH 3 CH 2 -C (O) NH-, and CH 3 CH 2 CH 2 -C(O)NH-。
In the present invention, the term "heteroaryl", alone or in combination, refers to a 5-to 20-membered (optionally 5-to 15-, 5-to 12-, 5-to 11-, 5-to 10-, 5-to 9-, 5-to 8-, 5-to 7-, 5-to 6-, 6-to 15-, or 6-to 9-membered) monocyclic or bicyclic or polycyclic group containing at least one aromatic ring having 1 or more (e.g., 1-6, or 1-to 4, or 1-to 3) heteroatoms independently selected from oxygen, nitrogen, and sulfur. Bicyclic or polycyclic heteroaryl groups include bicyclic, tricyclic or tetracyclic heteroaryl groups containing one ring that is an aromatic ring having one or more heteroatoms independently selected from O, S and N, and containing other rings that may be saturated, partially unsaturated or aromatic and may be carbocyclic or contain one or more heteroatoms independently selected from O, S and N. Examples of monocyclic heteroaryl groups include, but are not limited to, furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, tetrazolyl, and tri An oxazinyl group. Examples of bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, isoindolinyl, benzofuranyl, isobenzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazole, benzo [2,1,3 ]]Oxadiazolyl and benzo [2,1,3 ]]Thiadiazolyl and benzo [1,2,3 ]]Thiadiazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, oxazolopyridinyl, furopyridinyl, pteridinyl, purinyl, pyridopyridinyl, pyrazolo [1,5-a ]]Pyridinyl, pyrazolo [1,5-a ]]Pyrimidinyl, imidazo [1,2-a ]]Pyridyl, 1H-pyrrolo [3,2-b]Pyridyl, 1H-pyrrolo [2,3-b]Pyridinyl, pyrrolo [2,1-b]Thiazolyl and imidazo [2,1-b]Thiazolyl. Examples of tricyclic or polycyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, and xanthenyl. The heteroaryl group may be unsubstituted or substituted. Substituted heteroaryl refers to heteroaryl substituted one or more times (e.g., 1-4, 1-3, or 1-2) with a substituent, wherein the substituent is optionally selected from C 1 -C 3 Alkyl, C 3-6 Cycloalkyl, hydroxy, amino, mercapto, halogen, C 1 -C 3 Alkoxy, C 1 -C 3 Alkylamino, halo C 1 -C 3 Alkyl, amino C 1-3 Alkylene, C 1-3 alkyl-NHC (O) -, C 1-3 alkyl-C (O) NH-, cyano-, or any combination thereof.
In the present invention, the term "heteroarylene", alone or in combination, refers to a divalent aromatic ring radical containing at least one 5-to 20-membered (optionally 5-to 15-, 5-to 12-, 5-to 11-, 5-to 10-, 5-to 9-, 5-to 8-, 5-to 7-, 5-to 6-, 6-to 15-, or 6-to 9-membered) single or bicyclic or polycyclic ring having 1 or more (e.g., 1-to 6-, or 1-to 4-, or 1-to 3) heteroatoms independently selected from oxygen, nitrogen, and sulfur. Bicyclic or polycyclic heteroarylene includes bicyclic, tricyclic or tetracyclic heteroarylene groups containing one ring being an aromatic ring having one or more heteroatoms independently selected from O, S and N, and containingThe other rings may be saturated, partially unsaturated or aromatic and may be carbocyclic or contain one or more heteroatoms independently selected from O, S and N. Examples of monocyclic heteroarylene groups include, but are not limited to, furanylene, oxazolylene, isoxazolylene, oxadiazolylene, thiophenylene, thiazolylene, isothiazolylene, thiadiazolylene, pyrrolylene, imidazolylene, pyrazolylene, triazolylene, pyridinyl, pyrimidinylene, pyridazinylene, pyrazinylene, tetrazolylene, and triazinylene. Examples of bicyclic heteroarylenes include, but are not limited to, indolylene, isoindolylene, isoindolinylene, benzofuranylene, isobenzofuranylene, benzothienyl, indazolyl, benzimidazolylene, benzoxazolyl, benzisoxazolyl, benzothiazolylene, benzisothiazolylene, benzotriazole, benzo [2,1,3 ] ]Oxadiazolyl and benzo [2,1,3 ] phenylene]Thiadiazolyl, benzo [1,2,3 ] phenylene]Thiadiazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, oxazolopyridinyl, furanopyridinyl, pteridinyl, purinyl, pyridopyridinyl, pyrazolo [1,5-a ]]Pyridine subunit, pyrazolo [1,5-a ]]Pyrimidine subunit, imidazo [1,2-a]Pyridine subunit, 1H-pyrrolo [3,2-b]Pyridine subunit, 1H-pyrrolo [2,3-b]Pyridine subunit, pyrrolo [2,1-b]Thiazolylene and imidazo [2,1-b]Thiazole subunits. Examples of tricyclic or polycyclic heteroarylene groups include, but are not limited to, acriylene, benzindoylene, carbazolylene, dibenzofuranylene, and xanthylene. The heteroarylene group may be unsubstituted or substituted. Substituted heteroarylene means heteroarylene substituted one or more times (e.g., 1-4, 1-3, or 1-2 times) with a substituent optionally selected from C 1 -C 3 Alkyl, C 3-6 Cycloalkyl, hydroxy, amino, mercapto, halogen, C 1 -C 3 Alkoxy, C 1 -C 3 Alkylamino, halo C 1 -C 3 Alkyl, amino substituted C 1-3 Alkylene, C 1-3 alkyl-NHC (O) -, C 1-3 alkyl-C (O) NH-, cyano-, or any combination thereof.
Herein, a text isThe term "aryl" as used alone or in combination refers to a monovalent aromatic hydrocarbon radical containing 5 to 14 carbon atoms and optionally containing one or more fused rings, such as phenyl or naphthyl or fluorenyl. In the present disclosure, the "aryl" is an optionally substituted aryl. Substituted aryl means aryl substituted one or more times (e.g., 1-4, 1-3, or 1-2) with a substituent, such as aryl monosubstituted, disubstituted, or trisubstituted with a substituent, wherein the substituent is optionally selected from, for example, optionally deuterated C 1 -C 6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, hydroxy, amino, mercapto, halogen, cyano, oxo, optionally deuterated C 1 -C 6 Alkoxy, C 1 -C 4 Alkylamino, halo C 1 -C 6 Alkyl, amino substituted C 1-6 Alkylene, C 1-4 alkyl-NHC (O) -, C 1-4 alkyl-C (O) NH-, and any combination thereof.
In the present disclosure, the term "arylene" used alone or in combination refers to a divalent aromatic hydrocarbon group containing 5 to 14 carbon atoms and optionally containing one or more fused rings, such as phenylene or naphthylene or fluorenylene. In the present disclosure, the "arylene" is optionally substituted. Substituted arylene means arylene substituted one or more times (e.g., 1-4, 1-3, or 1-2) with a substituent, such as arylene monosubstituted, disubstituted, or trisubstituted with a substituent, wherein the substituent is optionally selected from, for example, deuterium, optionally deuterated C 1 -C 6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, hydroxy, amino, mercapto, halogen, cyano, oxo, optionally deuterated C 1 -C 6 Alkoxy, C 1 -C 4 Alkylamino, halo C 1 -C 6 Alkyl, amino substituted C 1-6 Alkylene, C 1-4 alkyl-NHC (O) -, C 1-4 alkyl-C (O) NH-, and any combination thereof.
The term "cycloalkyl" as used herein, alone or in combination, refers to a saturated or partially unsaturated (i.e., having one or more double bonds, but not being fully conjugated) monocyclic or bicyclic or polycyclic cycloalkyl group, which in some embodiments has 3 to 20Of carbon atoms (i.e. C 3-20 Cycloalkyl), or 3 to 15 carbon atoms (i.e., C 3-15 Cycloalkyl) 3 to 12 carbon atoms (i.e. C 3- 12 Cycloalkyl), or 3 to 11 carbon atoms (i.e., C 3-11 Cycloalkyl), or 3 to 10 carbon atoms (i.e., C 3-10 Cycloalkyl), or 3 to 8 carbon atoms (i.e., C 3-8 Cycloalkyl), or 3 to 7 carbon atoms (i.e., C 3-7 Cycloalkyl), or 3 to 6 carbon atoms (i.e., C 3-6 Cycloalkyl). The term "cycloalkyl" includes monocyclic, bicyclic, tricyclic or polycyclic cycloalkyl groups having 3 to 20 carbon atoms. Representative examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Bicyclic, tricyclic, and polycyclic cycloalkyl groups include bridged cycloalkyl groups (e.g., C 5-20 Bridged cycloalkyl, C 5-15 Bridged cycloalkyl and C 7-15 Bridged cycloalkyl), fused ring alkyl (e.g. C 5-20 Condensed ring alkyl, C 5-15 Condensed ring alkyl, C 6-20 Condensed ring alkyl, C 6-15 Condensed ring alkyl, C 7-20 Condensed ring alkyl, C 7-15 Condensed ring alkyl and C 8-15 Condensed ring alkyl groups) and spirocycloalkyl groups (e.g. C 5-20 Spirocycloalkyl, C 5-15 Spirocycloalkyl, C 6-20 Spirocycloalkyl, C 6-15 Spirocycloalkyl, C 7-20 Spirocycloalkyl, C 7-15 Spirocycloalkyl and C 8-15 Spirocycloalkyl), representative examples include, but are not limited to, decalinyl, octahydropentalenyl, octahydro-1H-indenyl, C 5-20 Spirocycloalkyl, C 5-15 Spirocycloalkyl, adamantyl, noradamantyl, bornyl, norbornyl (IUPAC system designation bicyclo [ 2.2.1)]Heptyl). Herein, the "cycloalkyl" is optionally mono-or poly-substituted, such as, but not limited to, 2-,2,3-,2,4-,2,5-, or 2, 6-disubstituted cyclohexyl. The substituent of the substituted "cycloalkyl" is optionally one or more (e.g., 1-5, 1-4, 1-3, 1-2, or 1) C selected from deuterium, optionally deuterated 1 -C 6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, hydroxy, amino, mercapto, halogen, cyano, oxo, optionally deuterated C 1 -C 6 Alkoxy, C 1 -C 4 Alkylamino, halo C 1 -C 6 Alkyl, amino substituted C 1-6 Alkylene, C 1-4 alkyl-NHC (O) -, C 1-4 alkyl-C (O) NH-, and substituents of any combination thereof. The term "C 3-6 Examples of cycloalkyl "include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexenyl, and cyclohexyl.
In the present invention, the term "cycloalkylene", alone or in combination, refers to a mono-or bi-or tri-or polycyclic hydrocarbon divalent radical having 3 to 20 carbon atoms (e.g., 3-15, 3-12, 3-11, 3-10, 3-8, 3-7, 3-6 carbon atoms) saturated and partially unsaturated (i.e., having one or more double bonds, but not fully conjugated). The term "cycloalkylene" includes monocyclic, bicyclic or tricyclic or polycyclic hydrocarbon divalent radicals having 3 to 20 (e.g., 3-15 or 3-12) carbon atoms. Representative examples of monocyclic cycloalkylene include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cyclohexenylene, cycloheptylene, and cyclooctylene. Bicyclic, tricyclic, and polycyclic cycloalkylene include bridged cycloalkyl (e.g., C 5-20 Bridged cycloalkyl, C 5-15 Bridged cycloalkyl and C 7-15 Bridged cycloalkyl), condensed ring alkylene (e.g. C 5-20 Alkylene condensed ring alkyl, C 5-15 Alkylene condensed ring alkyl, C 6-20 Alkylene condensed ring alkyl, C 6-15 Alkylene condensed ring alkyl, C 7-20 Alkylene condensed ring alkyl, C 7-15 Alkylene condensed ring alkyl and C 8-15 Condensed ring alkylene) and spirocycloalkyl (e.g. C 5-20 Spirocyclic alkylene radicals, C 5-15 Spirocyclic alkylene radicals, C 6-20 Spirocyclic alkylene radicals, C 6-15 Spirocyclic alkylene radicals, C 7-20 Spirocyclic alkylene radicals, C 7-15 Spirocyclic alkylene and C 8-15 Spirocycloalkylene), representative examples include, but are not limited to, decahydronaphthalenyl, octahydropentalene, octahydro-1H-indenylene, 2, 3-dihydro-1H-indenylene, C 5-20 Spirocyclic subunit, C 5-15 Spiroylene, adamantylene, noradamantylene, norbornylene (systematic name bicyclo [ 2.2.1)]Heptane subunits). At the bookIn the disclosure, the "cycloalkylene" is optionally mono-or poly-substituted, such as, but not limited to, 2-,2,3-,2,4-,2,5-, or 2, 6-disubstituted cyclohexyl. The substituent of the substituted "cycloalkylene" is optionally one or more C selected from deuterium, optionally deuterated 1 -C 6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, hydroxy, amino, mercapto, halogen, cyano, oxo, optionally deuterated C 1 -C 6 Alkoxy, C 1 -C 4 Alkylamino, halo C 1 -C 6 Alkyl, amino substituted C 1-6 Alkylene, C 1-4 alkyl-NHC (O) -, C 1-4 alkyl-C (O) NH-, and substituents of any combination thereof.
The term "C" used herein, alone or in combination x-y Spirocyclic alkylene "or" C x-y The spiroylene group (x and y are each integers) means a spiroylene group having x to y carbon atoms. The term "C" used in the present invention alone or in combination 7-11 Spirocycloalkyl "refers to a spirocycloalkyl group containing 7 to 11 (e.g., 7-10, 7-9) carbon atoms. The term "C 5-20 Spirocyclic alkylene "includes" C 5-15 Spirocyclic alkylene radicals C 7-15 Spirocyclic alkylene groups and C 7-20 Spirocyclic alkyls. The term "C 7-11 Representative examples of spirocycloalkyl groups include, but are not limited to, spiro [3.3 ]]Heptanylene, spiro [2.5 ]]Octane subunit, spiro [3.5 ]]Nonane subunit, spiro [4.4]Nonane subunit, spiro [4.5]Decane subunit or spiro [5.5 ]]Undecylenic subunit. The "C 7-11 The spirocycloalkyl group is optionally further substituted with one or more C's selected from deuterium, optionally deuterated 1 -C 6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, hydroxy, amino, mercapto, halogen, cyano, oxo, optionally deuterated C 1 -C 6 Alkoxy, C 1 -C 4 Alkylamino, halo C 1 -C 6 Alkyl, amino substituted C 1-6 Alkylene, C 1-4 alkyl-NHC (O) -, C 1-4 alkyl-C (O) NH-, and any combination thereof.
The term "hetero" as used herein, alone or in combination A cyclic group "or" heterocycloalkyl "refers to a 3 to 20 membered monocyclic, bicyclic, tricyclic, or polycyclic saturated or partially unsaturated (i.e., having one or more double bonds, but not fully conjugated) cyclic hydrocarbon group containing one or more (e.g., containing 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 1) heteroatoms independently selected from sulfur, oxygen, and nitrogen. In some embodiments, "heterocyclyl" may refer to a 3-to 15-membered (alternatively 3-to 14-membered, 3-to 12-membered, 3-to 11-membered, 3-to 10-membered, 3-to 9-membered, 3-to 8-membered, 3-to 7-membered, 3-to 6-membered, 3-to 5-membered, or 4-to 9-membered) saturated or partially unsaturated (i.e., having one or more double bonds, but not fully conjugated) cycloalkyl group containing one or more heteroatoms (e.g., containing 1-5 or 1-4, 1-3, 1-2 or 1) independently selected from sulfur, oxygen, and nitrogen. Examples of the term "heterocyclyl" include, but are not limited to, monocyclic heterocyclyl (e.g., 4 to 20 membered monocyclic heterocyclyl, and 4 to 15 membered monocyclic heterocyclyl), bridged heterocyclyl (e.g., 5 to 20 membered bridged heterocyclyl, 5 to 15 membered bridged heterocyclyl, 7 to 20 membered bridged heterocyclyl, and 7 to 15 membered bridged heterocyclyl), fused heterocyclyl (e.g., 5 to 20 membered fused heterocyclyl, and 5 to 15 membered fused heterocyclyl), spiro heterocyclyl (e.g., 5 to 20 membered spiro heterocyclyl, and 5 to 15 membered spiro heterocyclyl), cyclic ester groups (i.e., lactones (Lactone), e.g., 4 to 15 membered, 4 to 14 membered, 4 to 13 membered, 4 to 12 membered, 4 to 11 membered, 4 to 10 membered, 4 to 9 membered, 4 to 8 membered, 5 to 15 membered, 5 to 10 membered, 5 to 8 membered, 6 to 15 membered, or 6 to 10 membered cyclic ester groups) and cyclic amide groups (i.e.g., lactams, e.g., 4 to 15 membered, 4 to 14 membered, 4 to 13 membered, 4 to 12 membered, 4 to 11, 4 to 10 membered, 4 to 9 membered, 4 to 10 membered, 5 to 10 membered amide groups). Representative examples of monocyclic heterocyclyl groups include, but are not limited to, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, azepanyl, azacyclooctyl, diazepanyl (e.g., 1, 4-diazepan-1-yl), and diazepanyl. Bicyclic, tricyclic and polycyclic heterocyclic groups include bridged heterocyclic groups, fused heterocyclic groups and spiro heterocyclic groups Representative examples of radicals include, but are not limited to, 6-azabicyclo [3.1.1]Heptan-3-yl, 2, 5-diazabicyclo [2.2.1]Heptan-2-yl, 3, 6-diazabicyclo [3.1.1]Heptan-3-yl, 3-azabicyclo [3.2.1]Octane-8-yl, 3, 8-diazabicyclo [3.2.1]Octane-8-yl, 3, 8-diazabicyclo [3.2.1]Octan-3-yl, 2, 5-diazabicyclo [2.2.2]Octan-2-yl, and azaspirocyclic groups (e.g., 5-to 20-membered azaspirocyclic groups, such as 3-azaspiro [5.5 ]]Undec-3-yl). The heterocyclic group may be unsubstituted or substituted as well defined (e.g. mono-, di-, tri-, or polysubstituted), wherein the substituents are optionally selected from deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, oxo, optionally deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, C 1-4 alkyl-NH-, NH 2 -C 1-6 Alkylene, C 1-4 alkyl-NHC (O) -, C 1-4 alkyl-C (O) NH-, and any combination thereof.
The term "nitrogen-containing monocyclic heterocyclyl", as used herein, alone or in combination, refers to a 3 to 20 membered (optionally 3 to 15 membered, 3 to 14 membered, 3 to 12 membered, 3 to 11 membered, 3 to 10 membered, 3 to 9 membered, 3 to 8 membered, 3 to 7 membered, 3 to 6 membered, 3 to 5 membered, or 4 to 9 membered) monocyclic saturated or partially unsaturated (i.e. having one or more double bonds, but not fully conjugated) monovalent cyclic hydrocarbon groups containing one nitrogen atom and optionally containing one or more heteroatoms (e.g. containing 1 to 5, 1 to 4, 1 to 2 or 1) independently selected from sulfur, oxygen and nitrogen. Representative examples of nitrogen-containing monocyclic heterocycles include, but are not limited to, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, diazepinyl (e.g., 1, 4-diazepin-1-yl), and diazepinyl. The nitrogen-containing monocyclic heterocyclic group may be unsubstituted or substituted (e.g., mono-, di-, tri-, or polysubstituted) as well-defined, wherein the substituents are optionally selected from deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, oxo, optionally deuterated C 1-6 Alkyl group,Halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, C 1-4 alkyl-NH-, NH 2 -C 1-6 Alkylene, C 1-4 alkyl-NHC (O) -, C 1-4 alkyl-C (O) NH-, and any combination thereof.
The term "nitrogen-bridged heterocyclyl", as used herein, alone or in combination, refers to a 3 to 20 membered (optionally 3 to 15 membered, 3 to 14 membered, 3 to 12 membered, 3 to 11 membered, 3 to 10 membered, 3 to 9 membered, 3 to 8 membered, 3 to 7 membered, 3 to 6 membered, 3 to 5 membered, or 4 to 9 membered) tricyclic saturated or partially unsaturated (i.e. having one or more double bonds, but not fully conjugated) monovalent cyclic hydrocarbon group containing one nitrogen atom and optionally containing one or more (e.g. 1 to 5, 1 to 4, 1 to 2, or 1) heteroatoms independently selected from sulfur, oxygen, and nitrogen. Tricyclic heterocyclyl groups include bridged heterocyclyl groups such as, but not limited to, 6-azabicyclo [3.1.1]Heptan-3-yl, 2, 5-diazabicyclo [2.2.1]Heptan-2-yl, 3, 6-diazabicyclo [3.1.1]Heptan-3-yl, 3-azabicyclo [3.2.1]Octane-8-yl, 3, 8-diazabicyclo [3.2.1]Octane-8-yl, 3, 8-diazabicyclo [3.2.1]Octan-3-yl and 2, 5-diazabicyclo [2.2.2]Octane-2-yl. The nitrogen-containing bridged heterocyclic group may be unsubstituted or substituted as well defined (e.g., mono-, di-, tri-, or polysubstituted), wherein the substituents are optionally selected from deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, oxo, optionally deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, C 1-4 alkyl-NH-, NH 2 -C 1-6 Alkylene, C 1-4 alkyl-NHC (O) -, C 1-4 alkyl-C (O) NH-, and any combination thereof.
The term "heterocyclylene" or "heterocycloalkylene", as used herein, alone or in combination, refers to a 3 to 20 membered monocyclic, bicyclic, tricyclic, or polycyclic saturated or partially unsaturated (i.e., having one or more double bonds, but not fully conjugated) divalent cyclic hydrocarbon group containing one or more (e.g., containing 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 1) heteroatoms independently selected from sulfur, oxygen, and nitrogen.In some embodiments, "heterocyclyl" may refer, for example, to a 3-to 15-membered (alternatively 3-to 14-membered, 3-to 12-membered, 3-to 11-membered, 3-to 10-membered, 3-to 9-membered, 3-to 8-membered, 3-to 7-membered, 3-to 6-membered, 3-to 5-membered, or 4-to 9-membered) divalent cyclic hydrocarbon group containing one or more (e.g., containing 1-5 or, 1-4, 1-3, 1-2, or 1) heteroatoms independently selected from sulfur, oxygen, and nitrogen. Examples of the term "heterocyclylene" include, but are not limited to, monocyclic heterocyclylene (e.g., 4 to 20 membered monocyclic heterocyclylene, and 4 to 15 membered monocyclic heterocyclylene), bridged heterocyclylene (e.g., 5 to 20 membered bridged heterocyclylene, 5 to 15 membered bridged heterocyclylene, 7 to 20 membered bridged heterocyclylene, and 7 to 15 membered bridged heterocyclylene), fused heterocyclylene (e.g., 5 to 20 membered fused heterocyclylene, and 5 to 15 membered fused heterocyclylene), spiro heterocyclylene (e.g., 5 to 20 membered spiro heterocyclylene, and 5 to 15 membered spiro heterocyclylene), cyclic ester subunits (i.e., lactone), such as 4 to 15 membered, 4 to 14 membered, 4 to 13 membered, 4 to 12 membered, 4 to 11 membered, 4 to 10 membered, 4 to 9 membered, 4 to 8 membered, 5 to 15 membered, 5 to 10 membered, 5 to 8 membered, 6 to 15 membered or 6 to 10 membered cyclic ester subunits) and cyclic amide subunits (i.e.e., lactamide, such as 4 to 15, 14 to 14 membered, 4 to 12 membered, 4 to 11 membered, 4 to 10 membered, 6 to 10 membered cyclic amide, 10 to 10 membered amide. Representative examples of monocyclic heterocycloalkylene groups include, but are not limited to, azetidinylene, oxetylene, pyrrolidinylene, imidazolidinylene, pyrazolidinylene, tetrahydrofuranylene, tetrahydropyranyl, tetrahydrothiopyranylene, oxazolidinylene, thiazolidinylene, piperidylene, piperazinylene, morpholinylene, thiomorpholinylene, dioxanyl, and diazepanylene groups (e.g., 1, 4-diazepanylene, 4, 5-diazepanylene, 1, 3-diazepanylene). Bicyclic heterocyclylene, tricyclic heterocyclylene, and polycyclic heterocyclylene include bridged heterocyclylene, fused heterocyclylene, and spiro heterocyclylene, for example, but not limited to, representative examples include, but are not limited to, 6-azabicyclo [3.1.1 ]Heptane subunit, 2, 5-diazabicyclo [2.2.1]Heptane subunit, 36-diazabicyclo [3.1.1]Heptanylene, 3-azabicyclo [3.2.1]Octane subunit, 3, 8-diazabicyclo [3.2.1]Octane subunit, 3, 8-diazabicyclo [3.2.1]Octane subunit, 2, 5-diazabicyclo [2.2.2]Octane subunit, and azaspiro-groups (e.g., 5-to 20-membered azaspiro-groups, e.g., 3-azaspiro [5.5 ]]Undecylen). The heterocyclic group may be unsubstituted or substituted (e.g. mono-, di-, tri-, or polysubstituted) as defined, wherein the substituents are selected from deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, oxo, optionally deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, C 1-4 alkyl-NH-, NH 2 -C 1-6 Alkylene, C 1-4 alkyl-NHC (O) -, C 1-4 alkyl-C (O) NH-, and any combination thereof.
The term "nitrogen-containing monocyclic heterocyclylene" as used herein, alone or in combination, refers to a 3 to 20 membered (optionally 3 to 15 membered, 3 to 14 membered, 3 to 12 membered, 3 to 11 membered, 3 to 10 membered, 3 to 9 membered, 3 to 8 membered, 3 to 7 membered, 3 to 6 membered, 3 to 5 membered, or 4 to 9 membered) monocyclic saturated or partially unsaturated (i.e. having one or more double bonds, but not fully conjugated) divalent cyclic hydrocarbon groups containing one nitrogen atom and optionally containing one or more (e.g. containing 1 to 5, 1 to 4, 1 to 2 or 1) heteroatoms independently selected from sulfur, oxygen and nitrogen. Representative examples of nitrogen-containing monocyclic heterocycles include, but are not limited to, piperidinyl, piperazinyl, morpholinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, thiomorpholinyl, azepanyl, diazepinyl, azepanyl, and diazepinyl. The nitrogen-containing monocyclic heterocyclylene may be unsubstituted or substituted (e.g., mono-, di-, tri-, or polysubstituted) as well-defined, wherein the substituents are optionally selected from deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, oxo, optionally deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy radicalRadical, C 1-4 alkyl-NH-, NH 2 -C 1-6 Alkylene, C 1-4 alkyl-NHC (O) -, C 1-4 alkyl-C (O) NH-, and any combination thereof.
The term "nitrogen-containing bridged heterocyclyl", as used herein, alone or in combination, refers to a 3 to 20 membered (optionally 3 to 15 membered, 3 to 14 membered, 3 to 12 membered, 3 to 11 membered, 3 to 10 membered, 3 to 9 membered, 3 to 8 membered, 3 to 7 membered, 3 to 6 membered, 3 to 5 membered, or 4 to 9 membered) tricyclic saturated or partially unsaturated (i.e. having one or more double bonds, but not fully conjugated) divalent cyclic hydrocarbon group containing one nitrogen atom and optionally containing one or more (e.g. 1 to 5, 1 to 4, 1 to 2 or 1) heteroatoms independently selected from sulfur, oxygen and nitrogen. Tricyclic heterocyclylene groups include bridged heterocyclylene groups such as, but not limited to, 6-azabicyclo [3.1.1]Heptane subunit, 2, 5-diazabicyclo [2.2.1]Heptane subunit, 3, 6-diazabicyclo [3.1.1 ]]Heptanylene, 3-azabicyclo [3.2.1]Octane subunit, 3, 8-diazabicyclo [3.2.1]Octane subunit, 3, 8-diazabicyclo [3.2.1]Octane subunit and 2, 5-diazabicyclo [2.2.2]Octane subunit. The nitrogen-containing bridged heterocyclyl may be unsubstituted or substituted as well defined (e.g. mono-, di-, tri-, or polysubstituted), wherein the substituents are optionally selected from deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, oxo, optionally deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, C 1-4 alkyl-NH-, NH 2 -C 1-6 Alkylene, C 1-4 alkyl-NHC (O) -, C 1-4 alkyl-C (O) NH-, and any combination thereof.
The term "alkenylene", as used herein, alone or in combination, refers to a straight or branched chain divalent hydrocarbon radical containing 2 to 8 carbon atoms (e.g., 2 to 6, 2 to 5 carbon atoms, or 2 to 4, 2 to 3, or 2 carbon atoms) having one or more (e.g., 1 to 3, 1 to 2, or 1) carbon-carbon double bonds. Examples of alkenylene groups include, but are not limited to, vinylidene (e.g., -ch=ch-), 1-propenylene, allylene, 1-butenylene, 2-butenylene, 3-butenylene, isobutenylene, pentenylene, n-penta-2, 4-dienylene, 1-methyl-but-1-enylene, 2-methyl-but-1-enylene, 3-methyl-but-1-enylene, 1-methyl-but-2-enylene, 2-methyl-but-2-enylene, 3-methyl-but-2-enylene, 1-methyl-but-3-enylene, 2-methyl-but-3-enylene, 3-methyl-but-3-enylene, and hexenylene.
As used herein, the term "Borneolum Syntheticum" or "bornane" (also known as 1, 7-trimethylyclo [ 2.2.1)]A heptane; camphane; born ane) has a definition known to those skilled in the art. As used herein, the term "bornyl" or "borneol" refers to a monovalent radical of a bornane, i.e., the radical remaining after any hydrogen in the bornane has been removed. Representative examples of "ice flakes" include, but are not limited to, 1, 7-trimethylbicyclo [2.2.1 ]Heptan-2-yl, 1, 7-trimethylbicyclo [2.2.1]Heptan-3-yl, 1, 7-trimethylbicyclo [2.2.1]Heptane-4-yl, 1, 7-trimethylbicyclo [2.2.1]Heptane-5-yl, or 1, 7-trimethylbicyclo [2.2.1]Heptane-6-yl,
In this context, the term "bicyclo [2.2.1] heptane" (also known as bicyclo [2.2.1] heptane) or "norbornane" has the definition known to the person skilled in the art. As used herein, "bicyclo [2.2.1] heptyl" or "norbornyl" refers to a monovalent group of bicyclo [2.2.1] heptane, i.e., the group remaining after any hydrogen in the bicyclo [2.2.1] heptane has been removed. Representative examples of "bicyclo [2.2.1] heptanyl" include, but are not limited to, bicyclo [2.2.1] heptan-2-yl, bicyclo [2.2.1] heptan-3-yl, bicyclo [2.2.1] heptan-4-yl, bicyclo [2.2.1] heptan-5-yl, or bicyclo [2.2.1] heptan-6-yl.
The term "bicyclo [2.2.1] heptene" is also referred to herein as bicyclo [2.2.1] thiophene) and has a definition known to those skilled in the art. As used herein, "bicyclo [2.2.1] heptenyl" refers to a monovalent group of a bicyclo [2.2.1] heptene, i.e., the group remaining after any hydrogen in the bicyclo [2.2.1] heptene is removed. Representative examples of "bicyclo [2.2.1] heptenyl" include, but are not limited to, bicyclo [2.2.1] hept-5-en-2-yl, bicyclo [2.2.1] hept-5-en-3-yl, or bicyclo [2.2.1] hept-5-en-7-yl.
In this context, the term "adamantane" (also known as Tricyclo [3.3.1.1 ] 3,7 ]decane) has a definition known to those skilled in the art, the structural formula of which is for example as follows:herein, "adamantyl" refers to a monovalent group of adamantane, i.e., a group remaining after any hydrogen in adamantane is removed. Representative examples of "adamantyl" include, but are not limited to, 1-adamantyl, 2-adamantyl, 3-adamantyl, 4-adamantyl, 5-adamantyl, 6-adamantyl, 7-adamantyl, 8-adamantyl, 9-adamantyl, or 10-adamantyl.
In this context, the term "noradamantane" (also known as noramantadine, or octahydro-2,5-methanopentalene (translation: octahydro-2, 5-methanopentalene)) has a definition known to the person skilled in the art, the structural formula of which is for example as follows:in this context, "noradamantyl" refers to a monovalent group of noradamantane, i.e., the group remaining after any hydrogen in the noradamantane has been removed. Representative examples of "adamantyl" include, but are not limited to, 1-adamantyl, 2-adamantyl, 3-adamantyl, 4-adamantyl, 5-adamantyl, 6-adamantyl, 7-adamantyl, 8-adamantyl, or 9-adamantyl.
Salts or pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs of the compounds of formula (I), formula (II) or formula (III) are also encompassed within the scope of the present disclosure.
In all embodiments of the present disclosure, the salt or pharmaceutically acceptable salt of the compound of formula (I), formula (II) or formula (III) refers to non-toxic inorganic or organic acid and/or base addition salts. Examples include: sulfate, hydrohalate (including hydrochloride, hydrobromide), maleate, sulfonate, citrate/citrate, lactate, lactobionate, L-tartrate, fumarate, L-malate, L-lactate, alpha-ketoglutarate, hippurate, D-glucuronate, D-gluconate, alpha-D-glucoheptonate, glycolate, mucinate, L-ascorbate, orotate, picrate, glycinate, alaninate, arginate, cinnamate, laurate, pamoate, sebacate, benzenesulfonate, methanesulfonate, ethanesulfonate, ethanedisulfonate, formate, acetate, 2-dichloroacetate, trimethylacetate, propionate, valerate, palmitate, triphenylacetate, 2-ethyl-succinate, iodate, nicotinate, L-pyroglutamate, L-proline, ferulate, 2-hydroxyethanesulfonate, nitrate, gentisate, cholate, salicylate, terephthalate, glutarate, adipate, stearate, oleate, undecanoate, camphorsulfonate, dodecylsulfonate, phosphate, thiocyanate, dihydrogen phosphate, pyrophosphate, metaphosphate, oxalate, carbonate, malonate, benzoate, mandelate, succinate, pyruvate, p-chlorobenzenesulfonate, 1, 5-naphthalenedisulfonate, 3-hydroxy-2-naphthoate, 1-hydroxy-2-naphthoate, 2-naphthalenesulfonate, glycolate, p-toluenesulfonate, and the like.
By "pharmaceutically acceptable carrier" is meant a pharmaceutically acceptable material, such as a filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material, that carries or transports the compounds useful in the present disclosure into a patient or to a patient so that they can perform their intended function. Typically, such constructs are carried or transported from one organ or body part to another organ or body part. The carrier is compatible with the other ingredients of the formulation, including the compounds useful in this disclosure, and not deleterious to the patient, and must be "acceptable". Some examples of materials that may be used as pharmaceutically acceptable carriers include: sugars such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; diols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; surfactant phosphate buffer solution; and other non-toxic compatible substances used in pharmaceutical formulations.
The term "room temperature" of the present disclosure refers to the temperature of the surrounding environment, e.g., 20-30 ℃.
Herein, "stereoisomers" refer to compounds having the same chemical structure, but different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans), atropisomers, and the like.
As used herein, the term "solvate" refers to an association or complex of one or more solvent molecules and a compound of the present invention. Examples of solvents include water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term "hydrate" refers to a complex in which the solvent molecule is water.
In this context, the term "chiral" is a molecule having properties that do not overlap with its mirror image; and "achiral" refers to a molecule that may overlap with its mirror image.
In this context, the term "enantiomer" refers to two isomers of a compound that do not overlap but are in mirror image relationship to each other.
In this context, the term "diastereoisomer" refers to stereoisomers which have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, and reactivity. The diastereomeric mixture may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.
The term "oxo" or "oxo" used herein, alone or in combination, refers to = O.
The term "C (O)" or "C (=o)" or "c=o" used herein, alone or in combination, refers to a carbonyl group.
The term "C" used herein, alone or in combination x-y Spirocycloalkyl "(x and y are each integers) refers to spirocycloalkyl groups containing from x to y carbon atoms. The term "C" used in the present invention alone or in combination 7-11 Spirocycloalkyl "refers to a spirocycloalkyl group containing 7 to 11 carbon atoms. The term "C 5-15 Spirocyclic radicals "including" C 7-11 Representative examples of spirocycloalkyl "include, but are not limited to, spiro [3.3 ]]Heptyl, spiro [2.5 ]]Octyl, spiro [3.5 ]]Nonylalkyl, spiro [4.4 ]]Nonylalkyl, spiro [4.5 ]]Decyl or spiro [5.5 ]]Undecyl. The "C 7-11 The spirocycloalkyl group is optionally further selected from C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, deuterated C 1-3 Alkoxy, C 1-3 One or more of the substituents being alkylamino, amino, oxo, halo, hydroxy, cyano, or any combination thereof.
The term "C" used herein, alone or in combination x-y Bridged cycloalkyl "(x and y are each integers) refers to bridged cycloalkyl groups containing from x to y carbon atoms. The term "C" used in the present invention alone or in combination 7-11 Bridged cycloalkyl "means bridged cycloalkyl having 7 to 11 carbon atoms. The term "C 7-11 Representative examples of bridged cycloalkyl groups include, but are not limited to, adamantyl (amantamyl), noradamantyl, norbornyl (system named bicyclo [ 2.2.1)]Heptyl) and cubanyl (cubanyl). The "bridged cycloalkyl" is optionally substituted with 1 to 10 substituents selected from the group consisting of: c (C) 1-3 Alkyl, deuterated C 1- 3 Alkyl, C 1-3 Alkoxy, halogen, halogenated C 1-3 Alkyl, C 1-3 Alkylamino, amino, hydroxy, cyano, oxo, or any combination thereof.
In this context, "p-menthane" (also known as p-methane) has a definition known to those skilled in the art, and has the structural formula shown below, for example:as used herein, "p-menthyl" refers to a monovalent group of p-menthane, i.e., the group remaining after removal of any one of the hydrogens on the carbon at any position of the p-menthane. Representative examples include, but are not limited to
In this context, "m-menthane" (also known as m-methane) has a definition known to those skilled in the art, and has the structural formula shown below, for example:as used herein, "m-menthyl" refers to a monovalent group of m-menthane, i.e., the group remaining after any hydrogen on the carbon at any position of m-menthane has been removed. Representative examples include, but are not limited to
Herein, "Quinuclidine" (also known as Quinuclidine) is known by the chemical name 1-azabicyclo [2.2.2]Octane, having a definition known to those skilled in the art, has the structural formula shown below, for example:herein, "quinuclidinyl" refers to a monovalent group of the quinuclidine, i.e., the group remaining after removal of any one of the hydrogens on the carbon at any position of the quinuclidine. Representative examples include, but are not limited to
Examples
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. The present invention may be practiced without some or all of these specific details. In other instances, well known process operations have not been described in detail in order not to unnecessarily obscure the present invention. While the invention will be described in conjunction with the specific embodiments, it will be understood that they are not intended to limit the invention to these embodiments.
The following abbreviations are used throughout the specification and examples: acOH acetic acid aq. aqueous solution (aquos) Boc t-butoxycarbonyl BINAP 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine BPO benzoyl peroxide CAS Number (CAS No.; or Chemical Abstracts Service (CAS) Registry Number) Con. Concentration DCM dichloromethane DIAD azo dicarboxylic acid diisopropyl ester DIEA or DIPEA N, N-diisopropylethylamine DMF N, N-dimethylformamide DMSO dimethyl sulfoxide EA ethyl acetate EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride ESI electrospray ionization eq equivalent EtOH ethanol ethyl acetate EtOAc ethyl EtOAc HATU 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate HPLC high performance liquid chromatography HRMS high resolution LC-MS liquid chromatography-MS LC mass spectrometry combined with LRMS LC liquid chromatography-MS LC mass spectrometry liquid chromatography MeMeCN methyl MeCN acetonitrile MS N-bromosuccinimide NMO N-methylmorpholine oxide 1 H NMR Hydrogen Spectroscopy MeO-methoxy PE Petroleum ether rt room temperature tBu t-butyl TEA triethylamine TFA trifluoroacetic acid TLC TMS trimethylsilyl-OMs methanesulfonyloxy-ONs p-nitrobenzenesulfonyl-OT f trifluoromethanesulfonyloxy-OTs p-toluenesulfonyloxy
In the present invention, 1 the H NMR spectrum was measured using a Bruker-500MHz NMR apparatus using a CD containing 0.1% TMS as an internal standard 3 OD (δ=3.31 ppm) as solvent; or CDCl containing 0.1% TMS as an internal standard 3 (δ=7.26 ppm) as solvent; or DMSO-d containing 0.03% TMS (as internal standard) 6 (δ=2.50 ppm) as solvent; LC-MS spectra were measured on a Sciex API 2000 type mass spectrometer with an Agilent 1100 binary pump and DAD and ELSD or on an Agilent 1260-6125B single quadrupole liquid-mass spectrometer with an Agilent 1260 quaternary pump, DAD and ELSD, HPLC preparations on a SHIMADZU LC-20AP type instrument, HPLC purities on a SHIMADZU LC-30AP or Waters 1525 type instrument. All reactions were carried out under an air atmosphere unless specifically indicated; the reaction was followed by TLC or LC-MS.
The solvent and reagent treatments were as follows:
the solvents used for the reaction, DCM, DMF, anhydrous EtOH, anhydrous MeOH were all purchased from the national drug group; HPLC preparation is carried out using preparation grade CH 3 CN and deionized water; other substrates, reagents and drugs, unless specifically indicated, may be obtained by direct purchase from commercial sources or may be synthesized using or according to methods known in the art.
General synthetic method
The compounds described in this disclosure and/or pharmaceutically acceptable salts thereof can be synthesized using commercially available starting materials by synthetic techniques known in the art. The synthetic schemes described below exemplify the preparation of most compounds. The starting materials or reagents used in each scheme are commercially available or can be prepared by methods known to those skilled in the art. Salts, racemates, enantiomers, phosphates, sulphates, hydrochlorides and prodrug forms of the compounds of formula (I) of the present disclosure may be prepared by those skilled in the art according to conventional techniques in the art.
Synthesis scheme 1:
in scheme 1, ring A, (R) d1 ) m1 Ring B, (R) d2 ) m2 、(R a ) n X is as defined in the compounds of formula (I) of the present disclosure and in their various sub-embodiments, wherein ring A preferably represents cycloalkylene, heterocyclylene, heteroarylene or arylene. The group U of the substrate 1-1 represents a group capable of undergoing an amine alkylation reaction with an amino group, such as Br, cl, I, -OMs, -OTs, or-ONs. Ring C of substrate 1-2 represents a nitrogen-containing heterocyclic group, and W on ring C represents CH, -ch=or N.
The amine alkylation reaction in scheme 1 may be conventional techniques and methods well known to those skilled in the art. For example, the amine alkylation may be carried out in the presence of DIEA and sodium iodide, or triethylamine and sodium iodide at room temperature to 80 ℃.
For example, the operation of scheme 1 may be as follows:
substrate 1-1 (1.3 eq.) and substrate 1-2 (1.0 eq.) were dissolved in DMF followed by the addition of triethylamine (3.0 eq.) and sodium iodide (1.0 eq.) to the solution. The reaction solution was stirred at 50℃for 0.5-24 hours. LCMS detects completion of the reaction. Filtering the reaction solution, and separating and purifying the filtrate by using preparative high performance liquid chromatography to obtain the target compound.
Synthesis scheme 2:
in scheme 2, ring A, (R) d1 ) m1 Ring B, (R) d2 ) m2 、(R a ) n X is as defined in the compound of formula (I) and its various sub-embodiments of the present disclosure. Ring C of substrate 2-1 corresponds to X of the compounds of formula (I) of the present disclosure 1 Optionally substituted nitrogen-containing heterocyclyl groups are represented. The group U of substrate 2-2 represents a group capable of undergoing an amine alkylation reaction with an amino group, such as Br, cl, I, OMs, OTs, or ONs.
The amine alkylation reaction in scheme 2 may be conventional techniques and methods well known to those skilled in the art. For example, the amine alkylation may be carried out in the presence of DIEA and sodium iodide, or triethylamine and sodium iodide at room temperature to 80 ℃.
For example, the operation of scheme 2 may be as follows:
substrate 2-2 (1.3 eq.) and substrate 2-1 (1.0 eq.) were dissolved in DMF followed by the addition of triethylamine (3.0 eq.) and sodium iodide (1.0 eq.) to the solution. The reaction solution was stirred at 50℃for 0.5-24 hours. LCMS detects completion of the reaction. Filtering the reaction solution, and separating and purifying the filtrate by using preparative high performance liquid chromatography to obtain the target compound.
Synthesis scheme 3:
in scheme 3, ring A, (R) d1 ) m1 Ring B, (R) d2 ) m2 、(R a ) n X is as defined in the compound of formula (I) and its various sub-embodiments of the present disclosure. Ring D of compound 2-1 corresponds to L of the compound of formula (I) of the present disclosure 1 Optionally substituted C of the representation 6-10 Arylene, and ring C corresponds to X of a compound of formula (I) of the present disclosure 1 Optionally substituted nitrogen-containing heterocyclyl of the formula, W on ring C represents CH, -ch=or N. The radical W of substrate 3-2 1 Represents a group capable of undergoing an amine alkylation reaction with an amino group, such as Br, cl, I, OMs, OTs, or ONs.
The amine alkylation reaction in scheme 3 may be conventional techniques and methods well known to those skilled in the art. For example, the amine alkylation may be carried out in the presence of DIEA and sodium iodide, or triethylamine and sodium iodide at room temperature to 80 ℃.
For example, the operation of scheme 3 may be as follows:
Substrate 3-2 (1.3 eq.) and substrate 3-1 (1.0 eq.) were dissolved in DMF followed by the addition of triethylamine (3.0 eq.) and sodium iodide (1.0 eq.) to the solution. The reaction solution was stirred at 50℃for 0.5-24 hours. LCMS detects completion of the reaction. Filtering the reaction solution, and separating and purifying the filtrate by using preparative high performance liquid chromatography to obtain the target compound.
Synthesis scheme 4:
in scheme 4, ring A, (R) d1 ) m1 Ring B, (R) d2 ) m2 、(R a ) n X is as disclosed in formula (I)The compounds are defined in the various sub-embodiments. Ring D of compound 4-1 corresponds to L of the compound of formula (I) of the present disclosure 1 Optionally substituted C of the representation 6-10 Arylene, ring C corresponds to X of a compound of formula (I) of the present disclosure 1 Optionally substituted nitrogen-containing heterocyclyl of the formula, W on ring C represents CH, -ch=or N.
Depending on the target compound, the reaction substrate, reaction conditions (including reaction amount, temperature, time, etc.), post-treatment, etc. in the scheme 4 may be appropriately modified and adjusted by techniques and methods well known to those skilled in the art to obtain the desired target compound. For example, ring D may not be present depending on the target compound. The reductive amination reaction in scheme 4 can be conventional techniques and methods well known to those skilled in the art. For example, the reductive amination reaction may be carried out in the presence of sodium triacetoxyborohydride and 1, 2-dichloroethane, or sodium cyanoborohydride and 1, 2-dichloroethane, at a temperature of from room temperature to 80 ℃.
For example, the operation of scheme 4 may be as follows:
the substrate aldehyde 4-2 (1.3 eq.) and the substrate 4-1 (1.0 eq.) were dissolved in anhydrous 1, 2-dichloroethane and acetic acid (1 drop) was added to the solution. The reaction solution was stirred at 50 ℃ for 1 hour, then sodium borohydride acetate (2.0 eq.) was added to the solution, and the reaction solution was stirred for 1-24 hours. LCMS detects completion of the reaction. Filtering the reaction solution, and separating and purifying the filtrate by using preparative high performance liquid chromatography to obtain the target compound.
Synthesis scheme 5:
in scheme 5, ring A, (R) d1 ) m1 Ring B, (R) d2 ) m2 、(R a ) n X is as defined in the compounds of formula (I) of the present disclosure and in their various sub-embodiments, wherein ring A is preferably a cyclic hydrocarbon group having an unsaturated double bond, such as heteroaryl, aryl or cycloalkyl having an unsaturated double bond (e.g., cyclohexenyl). Ring C of substrate 5-2 corresponds to X of the compounds of formula (I) of the present disclosure 1 Optionally substituted heterocyclyl or cycloalkyl having a carbonyl group is represented.
The reductive amination reaction in scheme 5 can be conventional techniques and methods well known to those skilled in the art. For example, the reductive amination reaction may be carried out in the presence of sodium triacetoxyborohydride and 1, 2-dichloroethane, or sodium cyanoborohydride and 1, 2-dichloroethane, at a temperature of from room temperature to 80 ℃.
Synthesis scheme 6:
in scheme 6, ring A, (R) d1 ) m1 Ring B, (R) d2 ) m2 、(R a ) n X is as defined in the compounds of formula (I) of the present disclosure and in their various sub-embodiments, wherein ring A is preferably a cyclic hydrocarbon group having an unsaturated double bond, such as heteroaryl, aryl or cycloalkyl having an unsaturated double bond (e.g., cyclohexenyl). Ring C of substrate 6-2 corresponds to X of the compounds of formula (I) of the present disclosure 1 Optionally substituted nitrogen-containing heterocyclyl of the formula, W on ring C represents CH, -ch=or N. Substrate 6-2 may be the free base or a salt form thereof (e.g., hydrochloride, trifluoroacetate salt).
The amide condensation reaction in scheme 6 may be conventional techniques and methods well known to those skilled in the art. For example, the amide condensation reaction may be carried out in the presence of HATU, DIEA and DMF, or HOAt, EDCI, TEA and DCM at room temperature to 80 ℃.
For example, the operation of scheme 6 may be as follows:
substrate acid 6-1 (1.05 eq.) and substrate 6-2 (1.0 eq.) were dissolved in DMF followed by addition of HATU (1.5 eq.) and triethylamine (3.0 eq.) to the solution. The reaction solution was stirred at 50℃for 1-24 hours. LCMS detects completion of the reaction. Filtering the reaction solution, and separating and purifying the filtrate by using preparative high performance liquid chromatography to obtain the target compound.
Synthesis scheme 7:
In scheme 7, br can be in the 4-, 5-, 6-, or 7-position on the benzene ring of an isoindolinyl group, the resulting productThe hydroxymethyl group of (C) is also correspondingly located at the 4-, 5-, 6-, or 7-position on the benzene ring of the isoindolinyl group. A is as defined for compounds of formula (I) herein. (R) a ) n Represents the benzene ring is substituted by n R a Substituted, each R a Identical or different and each independently represents deuterium, fluorine, hydroxyl with a protecting group, mercapto with a protecting group, nitro, amino with a protecting group, cyano, optionally deuterated C 1-6 Alkyl, optionally deuterated C 1-6 Alkoxy, halo C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, C 2-6 Alkenyl, or C 2-6 Alkynyl; n represents an integer of 0, 1, 2, or 3.X is as defined in the compound of formula (I) and its various sub-embodiments of the present disclosure.
Scheme 7 the coupling reaction of step 1 may be conventional techniques and methods well known to those skilled in the art. For example, the coupling reaction may be carried out in the presence of tetrakis (triphenylphosphine) palladium and DMF at 40℃to 100 ℃. Scheme 7 the esterification reaction of step 2 can be conventional techniques and methods well known to those skilled in the art. Alternatively, the reaction substrate MsCl in the step 2 can be replaced by TsCl or NsCl according to the requirement, and the compound 7-2 is subjected to esterification reaction with TsCl or NsCl to prepare the corresponding target compound with OTs or ONs groups.
For example, the operation of scheme 7 may be as follows:
step 1: bromosubstrate 7-1 (1.0 eq.) and (tributyltin) methanol (1.5 eq.) were dissolved in DMF and tetrakis (triphenylphosphine) palladium (0.05 eq.) was added to the solution. At N 2 The reaction solution was heated to 100℃under protection and stirred for 48 hours. The reaction was checked for completion by thin layer chromatography. The reaction solution was cooled to 60℃and filtered while hot to remove black solids. The filtrate was concentrated under reduced pressure, and methylene chloride was added to the residue, followed by filtration to give a solid intermediate compound 7-2.
Step 2: the solid intermediate compound 7-2 (1.0 eq.) was dissolved in dimethyl sulfoxide/methylene chloride (1/9), and triethylamine (30.eq.) and methanesulfonyl chloride (1.5 eq.) were added to the reaction liquid in this order. The reaction solution was stirred at room temperature for 1 hour. The reaction was checked for completion by thin layer chromatography. Water is added into the reaction liquid, the mixture is filtered, the solid is washed by water, and the target compound is obtained after drying.
Synthesis scheme 8:
in scheme 8, br can be at the 4-, 5-, 6-, or 7-position on the benzene ring of the isoindolinyl group. (R) a ) n Represents the benzene ring is substituted by n R a Substituted, each R a Identical or different and each independently represents deuterium, fluorine, hydroxyl with a protecting group, mercapto with a protecting group, nitro, amino with a protecting group, cyano, optionally deuterated C 1-6 Alkyl, optionally deuterated C 1-6 Alkoxy, halo C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, C 2-6 Alkenyl, or C 2-6 Alkynyl; n represents an integer of 0, 1, 2, or 3.X is as defined in the compound of formula (I) and its various sub-embodiments of the present disclosure.
Scheme 8 the coupling reaction of step 1 may be conventional techniques and methods well known to those skilled in the art. For example, the coupling reaction may be carried out in the presence of a palladium catalyst and cesium carbonate at a temperature of 40℃to 100 ℃.
For example, the operation of scheme 8 may be as follows:
step 1: bromosubstrate 8-1 (1.0 eq.) and substrate 8-2 (1.5 eq.) were dissolved in N, N-dimethylformamide, and palladium catalyst (0.05 eq.) and cesium carbonate (2, 0 eq.) were added to the solution. At N 2 Under protection, the reaction solution is heated to 100 ℃ and stirred for 1-24 hours. The reaction was checked for completion by thin layer chromatography. The reaction solution was cooled to room temperature, washed with water, extracted with dichloromethane, and the organic phases were combined, dried, filtered and concentrated. The residue was purified by silica gel column chromatography to give intermediate 8-3.
Step 2: the intermediate product 8-3 obtained in the previous step was dissolved in methylene chloride, and trifluoroacetic acid was added. The reaction solution was stirred at room temperature for 2 hours. LCMS detected completion of the reaction, and the reaction mixture was concentrated under reduced pressure to afford the desired product 8-4.
Synthesis scheme 9:
in scheme 9, br can be at the 4-, 5-, 6-, or 7-position on the benzene ring of the isoindolinyl group. (R) a ) n Represents the benzene ring is substituted by n R a Substituted, each R a Identical or different and each independently represents deuterium, fluorine, hydroxyl with a protecting group, mercapto with a protecting group, nitro, amino with a protecting group, cyano, optionally deuterated C 1-6 Alkyl, optionally deuterated C 1-6 Alkoxy, halo C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, C 2-6 Alkenyl, or C 2-6 Alkynyl; n represents an integer of 0, 1, 2, or 3.X is as defined in the compound of formula (I) and its various sub-embodiments of the present disclosure. Scheme 9 the suzuki coupling of steps 1-3, the hydrogenation reduction reaction may be conventional techniques and methods well known to those skilled in the art.
For example, the operation of scheme 9 may be as follows:
step 1: bromosubstrate 9-1 (1.0 eq.) and substrate 9-2 (1.5 eq.) were dissolved in N, N-dimethylformamide, and palladium catalyst (0.05 eq.) and cesium carbonate (2, 0 eq.) were added to the solution. At N 2 Under protection, the reaction solution is heated to 100 ℃ and stirred for 1-24 hours. The reaction was checked for completion by thin layer chromatography. The reaction solution was cooled to room temperature, washed with water, extracted with dichloromethane, and the organic phases were combined, dried, filtered and concentrated. The residue was purified by silica gel column chromatography to give intermediate 9-3.
Step 2 of scheme 9-1: the intermediate product 9-3 obtained in the previous step was dissolved in tetrahydrofuran, palladium-carbon was added, the air in the reaction flask was replaced three times with hydrogen, and the reaction solution was heated to 50℃under a hydrogen atmosphere (1 atm) and stirred for 2 hours. LCMS detects completion of the reaction. The reaction solution was filtered and concentrated under reduced pressure to give intermediate 9-4.
Step 3 of scheme 9-1: intermediate product 9-4 obtained in the previous step was dissolved in dichloromethane, and trifluoroacetic acid was added. The reaction solution was stirred at room temperature for 2 hours. LCMS detected completion of the reaction, and the reaction mixture was concentrated under reduced pressure to give the desired product 9-5.
Step 2 of scheme 9-2: the intermediate product 9-3 obtained in the previous step was dissolved in methylene chloride, and trifluoroacetic acid was added. The reaction solution was stirred at room temperature for 2 hours. LCMS detected completion of the reaction, and the reaction mixture was concentrated under reduced pressure to afford the desired product 9-6.
Synthesis scheme 10:
in scheme 10, (R) a ) n And X is as defined in the compound of formula (I) and its various sub-embodiments of the present disclosure. The group U of the substrate 10-1 represents a group capable of undergoing a suzuki coupling reaction with the boric acid (ester) substrate 10-2, such as Br, cl, I, or OT f . The group Y of the boronic acid (ester) substrate 10-2 represents H or alkyl, and ring D corresponds to L of the compound of formula (I) of the present disclosure 1 Optionally substituted C of the representation 6-10 Arylene, and ring C corresponds to X of a compound of formula (I) of the present disclosure 1 Optionally substituted nitrogen-containing heterocyclyl of the formula, W on ring C represents CH, -ch=or N. The suzuki coupling reaction may be conventional techniques and methods well known to those skilled in the art, e.g. may be performed on Pd (dppf) Cl 2 ,K 2 CO 3 Is carried out at 60 to 80 ℃ in the presence of (C).
Synthesis scheme 11:
synthesis scheme 12:
synthesis scheme 13:
synthesis scheme 14:
in scheme 14, ring A, (R) d1 ) m1 Ring B, (R) d2 ) m2 As defined in the compounds of formula (I) and their various sub-embodiments of the present disclosure, wherein ring a is preferably a cyclic hydrocarbon group having an unsaturated double bond,such as heteroaryl, aryl, or cycloalkyl having an unsaturated double bond (e.g., cyclohexenyl). The group W of the substrate ester 14-1 represents a group capable of undergoing a suzuki coupling reaction with the boric acid (ester) substrate 14-2, such as Br, cl, I, or OT f . The group Y of the boric acid (ester) substrate 14-2 represents H or an alkyl group.
Synthesis scheme 15:
in scheme 15, ring A, (R) d1 ) m1 Ring B, (R) d2 ) m2 As defined in the compounds of formula (I) and their various sub-embodiments of the present disclosure, wherein ring a is preferably a cyclic hydrocarbon group having an unsaturated double bond, such as heteroaryl, aryl or cycloalkyl having an unsaturated double bond (e.g., cyclohexenyl). The group W of the substrate amine 15-1 represents a group capable of undergoing a suzuki coupling reaction with the boric acid (ester) substrate 15-2, such as Br, cl, I, or OT f . The group Y of the boric acid (ester) substrate 15-2 represents H or an alkyl group.
In some embodiments, the amino group of substrate amine 15-1 may be protected with a protecting group (e.g., boc), and the resulting product 15-3 may be further deprotected. Deprotection may be performed under conditions of HCl and ethyl acetate, or TFA and DCM.
Synthesis scheme 16:
in scheme 16, ring A, (R) d1 ) m1 Ring B, (R) d2 ) m2 Compounds of formula (I) and their various sub-embodiments as defined in the disclosure wherein ring a preferably represents cycloalkylene, heterocyclylene, heteroarylene or arylene. The group W of the substrate 16-1 represents a group capable of undergoing a suzuki coupling reaction with the boric acid (ester) substrate 16-2, such as Br, cl, I, or OT f . The group Y of the boric acid (ester) substrate 16-2 represents H or an alkyl group. Ring C of substrate 16-5 represents an optionally substituted nitrogen-containing heterocyclic group corresponding to group X of the compound of formula (I) of the present disclosure 1 。
SynthesisScheme 17:
in scheme 17, ring A, (R) d1 ) m1 Ring B, (R) d2 ) m2 Compounds of formula (I) and their various sub-embodiments as defined in the disclosure wherein ring a preferably represents cycloalkylene, heterocyclylene, heteroarylene or arylene. Ring C of substrate 17-3 represents an optionally substituted nitrogen-containing heterocyclic group corresponding to group X of the compound of formula (I) of the present disclosure 1 。
Scheme 17 the reductive amination reaction of step 1 and deprotection of step 2 can be conventional techniques and methods well known to those skilled in the art. For example, the reductive amination reaction may be carried out in the presence of sodium borohydride acetate and 1, 2-dichloroethane at room temperature to 80 ℃. Deprotection may be performed under TFA and DCM, or HCl and ethyl acetate.
For example, the operation of scheme 17 may be as follows:
step 1: aldehyde substrate 17-1 (1.0 eq.) and the corresponding amine substrate 17-2 (1.0 eq.) were dissolved in 1, 2-dichloroethane followed by the addition of sodium borohydride acetate (2.0 eq.). The reaction solution was heated to 80℃and stirred for 2 hours. The reaction was checked by thin layer chromatography and cooled to room temperature, quenched with water, extracted with dichloromethane, the organic phases combined, dried over anhydrous sodium sulfate, filtered and concentrated. Purifying the residue by silica gel column chromatography to obtain the product.
Step 2: the product obtained in the previous step is dissolved in dichloromethane, and trifluoroacetic acid is added. The reaction solution was stirred at room temperature for 2 hours. LCMS detects completion of the reaction and the reaction mixture is concentrated under reduced pressure to afford the desired product.
Synthesis scheme 18:
in scheme 18, ring A, (R) d1 ) m1 Ring B, (R) d2 ) m2 Compounds of formula (I) and sub-embodiments thereof as defined in the disclosure, wherein ring A preferably represents cycloalkylene, heterocyclylene Heteroaryl or arylene. Ring C of substrate 18-3 represents an optionally substituted nitrogen-containing heterocyclic group corresponding to group X of the compound of formula (I) of the present disclosure 1 。
Scheme 18 the oxidation reaction of step 1 may be conventional techniques and methods well known to those skilled in the art. For example, the oxidation reaction may be carried out under the conditions of sodium hypochlorite, sodium dihydrogen phosphate dihydrate and hydrogen peroxide. Scheme 18 the amide condensation reaction and deprotection of step 2 can be conventional techniques and methods well known to those skilled in the art. For example, the amide condensation reaction may be carried out in the presence of HATU and DIEA at room temperature to 80 ℃. Deprotection may be performed under TFA and DCM conditions.
For example, the operation of scheme 18 may be as follows:
step 1: aldehyde substrate 18-1 (1.0 eq.) was dissolved in acetonitrile and water, then sodium hypochlorite (1.5 eq.), sodium dihydrogen phosphate dihydrate (0.2 eq.) and hydrogen peroxide (10 eq.) were added. The reaction solution was stirred at room temperature for 16 hours. The reaction was checked for completion by thin layer chromatography. Saturated sodium carbonate solution is added into the reaction liquid, and petroleum ether is used for extraction. The aqueous phase was adjusted to ph=6 with dilute hydrochloric acid, extracted with dichloromethane, the organic phases combined, dried over anhydrous sodium sulfate, filtered and concentrated to give the intermediate product acid 18-2.
Step 2 (1) amide condensation reaction: the acid 18-2 (1.0 eq.) obtained in step 1, amine substrate 18-3 (1.2 eq.) was dissolved in N, N-dimethylformamide, followed by the addition of triethylamine (3.0 eq.) and HATU (1.5 eq.). The reaction solution was stirred at room temperature for 3 hours. The reaction was checked for completion by thin layer chromatography. The reaction solution was washed with water, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give an intermediate product.
Step 2 (2) deprotection: the product obtained in step 2 (1) was dissolved in methylene chloride, and trifluoroacetic acid was added. The reaction solution was stirred at room temperature for 2 hours. LCMS detects completion of the reaction. The reaction solution is concentrated under reduced pressure to obtain the target product 18-4.
Synthesis scheme 19:
in scheme 19, br can be at the 4-, 5-, 6-, or 7-position on the benzene ring of the isoindolinyl group. (R) a ) n Represents the benzene ring is substituted by n R a Substituted, each R a Identical or different and each independently represents deuterium, fluorine, hydroxyl with a protecting group, mercapto with a protecting group, nitro, amino with a protecting group, cyano, optionally deuterated C 1-6 Alkyl, optionally deuterated C 1-6 Alkoxy, halo C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, C 2-6 Alkenyl, or C 2-6 Alkynyl; n represents an integer of 0, 1, 2, or 3.X is as defined in the compounds of formula (I) and their sub-embodiments of the present disclosure. Scheme 19 the coupling reaction, deprotection of step 1-2, can be a conventional technique and process well known to those skilled in the art.
For example, the operation of scheme 19 may be as follows:
step 1: bromosubstrate 19-1 (1.0 eq.) and tert-butyl 3, 8-diazabicyclo [3.2.1]Octane-3-carboxylate (1.5 eq.) was dissolved in N, N-dimethylformamide, and palladium catalyst (0.05 eq.) and cesium carbonate (2, 0 eq.) were added to the solution. At N 2 Under protection, the reaction solution is heated to 100 ℃ and stirred for 1-24 hours. The reaction was checked for completion by thin layer chromatography. The reaction solution was cooled to room temperature, washed with water, extracted with dichloromethane, and the organic phases were combined, dried, filtered and concentrated. The residue was purified by silica gel column chromatography to give intermediate 19-2.
Step 2: intermediate product 19-2 obtained in the previous step was dissolved in methylene chloride, and trifluoroacetic acid was added. The reaction solution was stirred at room temperature for 2 hours. LCMS detected completion of the reaction, and the reaction mixture was concentrated under reduced pressure to afford the desired product 19-3.
Synthesis scheme 20:
synthesis scheme 21:
depending on the target compound, each of the above schemes and its reaction substrate, reaction conditions (including reaction amount, temperature, time, etc.), post-treatment, etc., may be appropriately modified and adjusted by techniques and methods well known to those skilled in the art to obtain the desired target compound, and the obtained target compound may be further modified by substituents, etc., according to methods well known to those skilled in the art to obtain other target compounds.
Examples
Intermediate example 1: preparation of 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03234)
The starting material methyl 2, 5-dimethylbenzoate (3.4 g,20.6 mmol) was dissolved in 100mL of carbon tetrachloride, and N-bromosuccinimide (8.0 g,45 mmol) and dibenzoyl peroxide (0.31 g,1.26 mmol) were added sequentially. The reaction mixture was refluxed at 80℃for 12h, cooled to room temperature, diluted with 100mL of petroleum ether, washed twice with water and once with saturated brine. The organic phase was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (eluent (v/v): EA/pe=0/1-1/20) to give methyl 2, 5-bis (bromomethyl) benzoate as an intermediate compound (white solid, 5.0g, yield: 76%).
Cesium carbonate (1.6 g,5 mmol) was added to a mixed solvent of 50mL of 1, 2-dichloroethane and 5mL of hexafluoroisopropanol, stirred at 65℃for 15min, and 3-amino-2, 6-piperidinedione hydrochloride (8.21 g,5 mmol) and methyl 2, 5-bis (bromomethyl) benzoate (1.6 g,5 mmol) were added in sequence, and stirred at 65℃for 12h. After the reaction was completed, the reaction mixture was cooled to room temperature and washed with water. The organic phase was separated, the solvent was removed by distillation under the reduced pressure, and the residue was separated by column chromatography over silica gel (eluent (v/v): meOH/dcm=0/1-1/10). The obtained product was further purified by beating with acetonitrile to obtain a white powder (455 mg, yield: 27%). 1 H NMR(500MHz,DMSO-d 6 )δ11.00(s,1H),7.78–7.66(m,2H),7.59(dd,J＝7.9,1.5Hz,1H),5.11(dd,J＝13.3,5.1Hz,1H),4.83(s,2H),4.47(d,J＝17.3Hz,1H),4.34(d,J＝17.4Hz,1H),2.91(ddd,J＝17.3,13.6,5.4Hz,1H),2.68–2.55(m,1H),2.39(qd,J＝13.3,4.5Hz,1H),2.01(dtd,J＝12.7,5.3,4.7,1.9Hz,1H).LCMS(ESI)m/z:C 14 H 14 BrN 2 O 3 + [M+H] + Calculated 337.0; found, 337.3.
Intermediate example 2:4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl]Preparation of 2-Formaldehyde (GTC 00947)
Step 1: preparation of 2-chloro-4, 4-dimethylcyclohex-1-en-1-carbaldehyde
POCl was added dropwise to a solution of DMF (4.9 mL,63.4 mmol) in DCM (100 mL) at-10deg.C 3 (5.5 mL,59.4 mmol) and after the completion of the dropwise addition, the reaction mixture was warmed to room temperature and 3, 3-dimethylcyclohex-1-one (5.5 mL,39.6 mmol) was added dropwise. The reaction was refluxed for 18 hours. The reaction was checked for completion by thin layer chromatography. The reaction mixture was cooled to room temperature and saturated NaHCO 3 The solution was quenched, the solution was washed with water (100 mL) and extracted with DCM (100 mL. Times.3). The combined organic phases were washed with saturated brine (50 ml×1), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=50/1) to give 2-chloro-4, 4-dimethylcyclohex-1-ene-1-carbaldehyde (5.9 g, yield: 86%) as a colorless oily compound. LCMS (ESI) C 9 H 14 ClO + [M+H] + Calculated, 173.07, found, 173.3.
Step 2: preparation of 4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbaldehyde
2-chloro-4, 4-dimethylcyclohex-1-ene-1-carbaldehyde (1.5 g,8.7 mmol) prepared in step 1, p-fluorobenzeneboronic acid (1.8 g,13.1 mmol) was dissolved in dioxane (30 mL), H 2 In O (3 mL), pd (dppf) Cl was added to the solution in sequence 2 (0.32 g,0.43 mmol) and K 2 CO 3 (2.4 g,17.4 mmol). N for air in reaction flask 2 The reaction mixture was stirred for 18 hours after three substitutions and heated to 90 ℃. The reaction was checked for completion by thin layer chromatography. The reaction solution was concentrated, and the residue was washed with water (100 mL), ethyl acetate(100 mL. Times.3) extraction. The combined organic phases were washed with saturated brine (50 ml×1), dried over anhydrous sodium sulfate and filtered. Concentrating the filtrate under reduced pressure, and purifying the residue with column chromatography (petroleum ether as eluent) to obtain pale yellow oily compound 4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl]-2-Formaldehyde (GTC 00947) (1.2 g, yield: 59%). 1 H NMR(400MHz,DMSO)δ9.39(s,1H),7.39–7.31(m,2H),7.25(ddd,J＝8.8,5.6,2.4Hz,2H),2.32(d,J＝2.0Hz,2H),2.30–2.23(m,2H),1.44(t,J＝6.4Hz,2H),0.97(s,6H)。LCMS(ESI):C 15 H 18 FO + [M+H] + Calculated, 233.13, found, 233.1.
Intermediate example 3:1- ((4 '-chloro- [1,1' -biphenyl)]Preparation of-2-yl) methyl) piperazine
Reference scheme 16 the process of step 3 prepares 1- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) piperazine.
Step 1:4- ((4 '-chloro- [1,1' -biphenyl)]Preparation of tert-butyl-2-yl-methyl) piperazine-1-carboxylate
To a solution of 2- (bromomethyl) -4 '-chloro-1, 1' -biphenyl (CAS number: 1001754-57-9) (0.8 g,2.8 mmol) and N-Boc-piperazine (0.8 g,4.3 mmol) in DCM (20 mL) was added TEA (1 mL,5.7 mmol). The reaction solution was stirred at room temperature for 2 hours. The reaction was checked for completion by thin layer chromatography. The reaction was washed with water (50 mL) and extracted with DCM (50 mL. Times.3). The combined organic phases were washed with saturated brine (50 ml×1), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=4/1 as eluent) to give compound 4- ((4 '-chloro- [1,1' -biphenyl) as a white solid ]-2-yl) methyl-piperazine-1-carboxylic acid tert-butyl ester (780 mg, yield: 71%). LC/MS (ESI) m/z C 22 H 28 ClN 2 O 2 + [M+H] + Calculated 387.2; found 387.2.
Step 2: preparation of 1- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) piperazine
To 4- ((4 '-chloro- [1,1' -biphenyl) obtained in step 3]To a solution of tert-butyl-2-yl-methyl-piperazine-1-carboxylate (780 mg,2.0 mmol) in dichloromethane (20 mL) was added HCl/dioxane (5 mL, 4M). The reaction solution was stirred at room temperature for 2 hours. LCMS detects completion of the reaction. The reaction solution is decompressed and concentrated to obtain white solid compound 1- ((4 '-chloro- [1,1' -biphenyl)]-2-yl) methyl piperazine (650 mg, yield: 100%). LC/MS (ESI) m/z C 17 H 20 ClN 2 + [M+H] + Calculated 287.2; found 287.2.
Intermediate example 4: preparation of 3- (1-oxo-5- (4- (piperazin-1-ylmethyl) phenyl) isoindolin-2-yl) piperidine-2, 6-dione
3- (1-oxo-5- (4- (piperazin-1-ylmethyl) phenyl) isoindolin-2-yl) piperidine-2, 6-dione was prepared according to the procedure of scheme 9, step 1.
Step 1 preparation of tert-butyl 4- (4- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) benzyl) piperazine-1-carboxylate
3- (5-bromo-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (CAS number: 1010100-26-1) (1 g,3.1 mmol), (4- ((4- (tert-butoxycarbonyl) piperazin-1-yl) methyl) phenyl) boronic acid (CAS number: 1190095-10-3) (1 g,3.1 mmol) was dissolved in dioxane (20 mL), and Pd (dppf) Cl was added to the solution in sequence 2 (0.23 g,0.31 mmol) and K 2 CO 3 (0.86 g,6.2 mmol). N for air in reaction flask 2 The reaction mixture was stirred for 18 hours after three substitutions and heated to 90 ℃. The reaction was checked for completion by thin layer chromatography. The reaction was filtered, the filtrate was concentrated under reduced pressure, the residue was washed with water (100 mL) and extracted with DCM (100 mL. Times.3). The combined organic phases were washed with saturated brine (50 ml×1), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent DCM/meoh=20/1) to give 4- (4- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) benzyl) piperazine-1-carboxylic acid tert-butyl ester (810 mg, yield: 51%) as a pale yellow solid. LC/MS (ESI) m/z C 29 H 35 N 4 O 5 + [M+H] + Calculated 519.3; found 519.3.
Step 2: preparation of 3- (1-oxo-5- (4- (piperazin-1-ylmethyl) phenyl) isoindolin-2-yl) piperidine-2, 6-dione
To a solution of tert-butyl 4- (4- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) benzyl) piperazine-1-carboxylate (810 mg,1.56 mmol) prepared in step 1 in dichloromethane (20 mL) was added a solution of HCl in dioxane (4 mL, 4M). The reaction solution was stirred at room temperature for 2 hours. LCMS detects completion of the reaction. The reaction solution was concentrated under reduced pressure to give 3- (1-oxo-5- (4- (piperazin-1-ylmethyl) phenyl) isoindolin-2-yl) piperidine-2, 6-dione (740 mg, yield: 104%) as a white solid. LC/MS (ESI) m/z C 24 H 27 N 4 O 3 + [M+H] + Calculated 419.2; found 419.2.
Intermediate example 5: preparation of (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl methane sulfonate
(2- (2, 6-Dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl methanesulfonate (20.0 g, yield: 86%, off-white solid) was prepared according to the procedure of scheme 7. LC/MS (ESI) m/z C 15 H 17 N 2 O 6 S + [M+H] + Calculated 353.08; found 353.1.
Intermediate example 6: preparation of (2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl methane sulfonate
(2- (2, 6-Dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methylsulfonate (1.1 g, yield: 86%, pale yellow solid) was prepared according to the method of scheme 7. LC/MS (ESI) m/z C 15 H 16 FN 2 O 6 S + [M+H] + Calculated 371.07; found 371.1.
Intermediate productsExample 7: preparation of (2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl methane sulfonate
(2- (2, 6-Dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methylsulfonate (1.1 g, yield: 86%, pale yellow solid) was prepared according to the method of scheme 7. LC/MS (ESI) m/z C 15 H 16 FN 2 O 6 S + [M+H] + Calculated 371.07; found 371.1.
Intermediate example 8: preparation of (2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl methane sulfonate
(2- (2, 6-Dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl methanesulfonate (6.5 g, yield: 82%, off-white solid) was prepared according to the procedure of scheme 7. LC/MS (ESI) m/z C 15 H 16 FN 2 O 6 S + [M+H] + Calculated 371.07; found 371.1.
Intermediate example 9: preparation of (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl methane sulfonate
(2- (2, 6-Dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl methanesulfonate (4.5 g, yield: 85%, off-white solid) was prepared according to the procedure of scheme 7. LC/MS (ESI) m/z C 15 H 17 N 2 O 6 S + [M+H] + Calculated 353.08; measured value 353.1
Intermediate example 10: preparation of 3- (1-oxo-5- (piperidin-4-ylmethyl) isoindolin-2-yl) piperidine-2, 6-dione (GT-3423)
3- (1-oxo-5- (piperidin-4-ylmethyl) isoindolin-2-yl) piperidine-2, 6-dione (3.2 g, yield: 83%, brown solid) was prepared according to the procedure of scheme 9. 1 H NMR(400MHz,DMSO)δ10.98(s,1H),9.01–8.55(m,2H),7.73–7.60(m,1H),7.51–7.41(m,1H),7.35(t,J＝7.4Hz,1H),5.11(dd,J＝13.2,5.1Hz,1H),4.38(dt,J＝32.5,16.6Hz,2H),3.21(d,J＝12.4Hz,2H),2.92(dt,J＝13.9,6.4Hz,1H),2.77(dd,J＝22.7,11.4Hz,2H),2.64(dd,J＝26.0,11.0Hz,3H),2.46–2.36(m,1H),2.07–1.77(m,3H),1.76–1.64(m,2H),1.48–1.28(m,2H).LC/MS(ESI)m/z:C 19 H 23 N 3 O 3 + [M+H] + Calculated 342.17; found 342.2.
Intermediate example 11: preparation of 3- (1-oxo-5- (piperazin-1-ylamino) isoindolin-2-yl) piperidine-2, 6-dione
3- (1-oxo-5- (piperazin-1-ylamino) isoindolin-2-yl) piperidine-2, 6-dione (1.6 g, yield: 91%, light brown solid) was prepared according to the procedure of scheme 8. 1 H NMR(400MHz,DMSO)δ11.09(s,1H),8.90(s,2H),7.37(d,J＝6.5Hz,2H),5.09(dd,J＝13.0,5.3Hz,1H),3.77(s,4H),3.44(s,4H),3.31(s,4H),3.21(s,4H),2.89(ddd,J＝17.5,14.2,5.4Hz,1H),2.64–2.52(m,2H),2.01(dd,J＝10.8,5.7Hz,1H).LC/MS(ESI)m/z:cal.C 17 H 21 N 5 O 3 + [M+H] + Calculated 344.2; found 344.2.
Intermediate example 12: preparation of 3- (5- (azetidin-3-ylamino) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione
3- (5- (azetidin-3-ylamino) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (2.5 g, yield: 97%, light brown solid) was prepared according to the procedure of scheme 8. 1 H NMR(400MHz,DMSO)δ10.95(s,1H),8.81(d,J＝40.1Hz,2H),7.39(d,J＝10.5Hz,1H),6.92(d,J＝4.8Hz,1H),6.79(d,J＝7.5Hz,1H),5.04(dd,J＝13.3,5.1Hz,1H),4.48(dd,J＝13.7,6.9Hz,1H),4.30(dd,J＝10.0,6.7Hz,3H),4.18(d,J＝16.9Hz,1H),4.06–3.97(m,2H),2.94–2.84(m,1H),2.59(d,J＝16.7Hz,1H),2.36(dt,J＝13.3,8.8Hz,1H),1.97(dd,J＝10.4,5.0Hz,1H).LC/MS(ESI)m/z:C 16 H 18 FN 4 O 3 + [M+H] + Calculated 333.2; found 333.1.
Intermediate example 13: preparation of 3- (5- (azetidin-3-ylmethylene) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione
Prepared according to the method of scheme 9-2 to give 3- (5- (azetidin-3-ylmethylene) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (730 mg, yield: 80%, brown solid). 1 H NMR(400MHz,DMSO)δ10.99(s,1H),9.08(s,2H),7.72(d,J＝7.9Hz,1H),7.42(s,1H),7.33(d,J＝7.7Hz,1H),6.56(s,1H),5.11(dd,J＝13.3,5.0Hz,1H),5.04(s,1H),4.80(s,2H),4.39(dd,J＝48.0,17.4Hz,2H),2.92(ddd,J＝18.6,13.6,5.4Hz,1H),2.61(dd,J＝32.9,14.6Hz,2H),2.46–2.28(m,1H),2.06–1.95(m,1H).LC/MS(ESI)m/z:C 17 H 18 N 3 O 3 + [M+H] + Calculated 312.13; found 312.2.
Intermediate example 14: preparation of 3- (5- (azetidin-3-ylmethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione
Prepared according to the method of scheme 9-1 in scheme 9 to give 3- (5- (azetidin-3-ylmethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (1.3 g, yield: 69%, brown solid). 1 H NMR(400MHz,DMSO)δ10.98(s,1H),8.60(d,J＝36.3Hz,2H),7.68(d,J＝7.8Hz,1H),7.44(s,1H),7.35(d,J＝8.1Hz,1H),5.10(dd,J＝13.3,5.0Hz,1H),4.47–4.26(m,2H),3.96(s,2H),3.74(s,2H),3.10(dd,J＝15.3,7.4Hz,1H),3.04(d,J＝7.7Hz,2H),2.98–2.84(m,1H),2.60(d,J＝17.8Hz,1H),2.40(dt,J＝13.6,9.0Hz,2H),2.01(s,1H).LC/MS(ESI)m/z:C 17 H 20 N 3 O 3 + [M+H] + Calculated 314.15; found 314.2.
Intermediate example 15: preparation of 3- (5- (hydroxy (3-hydroxyazetidin-3-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione
3- (5- (hydroxy (3-hydroxyazetidin-3-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione was prepared according to the procedure of scheme 11.
Step 1:
tert-butyl 3- ((2- (2, 6-Dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methylene) azetidine-1-carboxylic acid ester (2 g,4.86 mmol) was dissolved in THF (10 mL) and H 2 To the solution was added potassium osmium (180 mg,0.49 mmol) and N-methylmorpholine N-oxide (1.14 g,9.72 mmol) in O (10 mL). The reaction solution was stirred at room temperature for 18 hours. The reaction was checked for completion by thin layer chromatography. The reaction was quenched with saturated sodium metabisulfite (50 mL) and extracted with ethyl acetate (50 mL. Times.3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give tert-butyl 3- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) (hydroxy) methyl) -3-hydroxyazetidine-1-carboxylate (1.5 g, yield: 69%) as a brown solid. LC/MS (ESI) m/z C 22 H 28 N 3 O 7 + [M+H] + Calculated 446.19; actual measurement value [ M+H-56 ]] + 390.2.
Step 2:
to a solution of tert-butyl 3- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) (hydroxy) methyl) -3-hydroxyazetidine-1-carboxylate (1.5 g,3.37 mmol) in dichloromethane (30 mL) was added TFA (10 mL). The reaction solution was stirred at room temperature for 18 hours. LCMS detects completion of the reaction. The reaction mixture was concentrated under reduced pressure, ethyl acetate/petroleum ether (20 mL, 1/1 by volume) was added to the residue, and a solid was separated out . The turbid liquid was filtered, and the objective compound (1 g, brown solid, yield: 67%) was obtained. 1 H NMR(400MHz,DMSO)δ10.99(s,1H),8.66(d,J＝68.6Hz,2H),7.69(d,J＝7.9Hz,1H),7.60(d,J＝6.5Hz,1H),7.55–7.46(m,1H),6.45(s,1H),6.26(s,1H),5.12(dd,J＝8.6,3.4Hz,1H),4.38(dd,J＝53.5,17.2Hz,2H),4.19(d,J＝31.0Hz,2H),3.79(s,1H),3.57(s,1H),2.91(dd,J＝21.6,9.5Hz,1H),2.63(t,J＝16.5Hz,1H),2.45–2.30(m,3H),2.01(s,1H).LC/MS(ESI)m/z:C 17 H 20 N 3 O 5 + [M+H] + Calculated 346.14; found 346.2.
Intermediate example 16: preparation of 3- (1-oxo-5- (4- (piperazin-1-ylmethyl) phenyl) isoindolin-2-yl) piperidine-2, 6-dione
3- (1-oxo-5- (4- (piperazin-1-ylmethyl) phenyl) isoindolin-2-yl) piperidine-2, 6-dione (740 mg, yield: 104%, white solid) was prepared according to the method of scheme 10. LC/MS (ESI) m/z C 24 H 27 N 4 O 3 + [M+H] + Calculated 419.26; found 419.3.
Intermediate example 17:3- (5- (3, 8-diazabicyclo [ 3.2.1)]Preparation of octane-8-yl) -1-oxo-isoindolin-2-yl piperidine-2, 6-dione
Preparation of 3- (5- (3, 8-diazabicyclo [ 3.2.1) by the method of scheme 19]Octane-8-yl) -1-oxo-isoindolin-2-yl) piperidine-2, 6-dione (0.76 g, yield: 82%, light brown solid). 1 H NMR(400MHz,DMSO)δ10.95(s,1H),9.25(d,J＝47.8Hz,2H),7.58(d,J＝8.3Hz,1H),7.24–6.91(m,2H),5.05(dd,J＝13.0,4.5Hz,1H),4.54(s,2H),4.27(dt,J＝26.0,13.0Hz,2H),3.08(s,4H),2.90(t,J＝12.8Hz,1H),2.59(d,J＝17.0Hz,1H),2.44–2.31(m,1H),2.19–1.87(m,5H).LC/MS(ESI)m/z:C 19 H 22 N 4 O 3 + [M+H] + Calculated 355.17; found 355.2.
Intermediate example 18: preparation of 3- (1-oxo-5- (piperazin-1-ylmethyl) isoindolin-2-yl) piperidine-2, 6-dione
3- (1-oxo-5- (piperazin-1-ylmethyl) isoindolin-2-yl) piperidine-2, 6-dione was prepared according to the method of scheme 12.
Step 1:
(2- (2, 6-Dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl methanesulfonate (1.0 g,2.84 mmol), N-Boc-piperazine (1.06 g,5.68 mmol) was dissolved in anhydrous DCM (40 mL), and diisopropylethylamine (1.18 mL,8.5 mmol) and sodium iodide (0.43 g,2.84 mmol) were added to the reaction solution. The reaction solution was stirred at room temperature for 18 hours. The reaction was checked for completion by thin layer chromatography. The reaction was washed with water (50 mL) and extracted with DCM (50 mL. Times.3). The combined organic phases were washed with saturated brine (50 ml×1), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to give tert-butyl 4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazine-1-carboxylate (780 mg, yield: 71%) as a white solid. LC/MS (ESI) m/z C 23 H 31 N 4 O 5 + [M+H] + Calculated 443.2; found 443.2.
Step 2:
tert-butyl 4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazine-1-carboxylate (780 mg,2.0 mmol) was dissolved in dichloromethane (20 mL) and hydrochloric acid/dioxane solution (5.2 mL, 4M) was added to the solution. The reaction solution was stirred at room temperature for 2 hours. LCMS detects completion of the reaction. The reaction solution was concentrated under reduced pressure to give 3- (1-oxo-5- (piperazin-1-ylmethyl) isoindolin-2-yl) piperidine-2, 6-dione (910 mg, yield: 105%) as a white solid. LC/MS (ESI) m/z C 18 H 23 N 4 O 3 + [M+H] + Calculated 343.2; found 343.2.
Intermediate example 19: preparation of 3- (1-oxo-5- (piperidin-4-ylamino) isoindolin-2-yl) piperidine-2, 6-dione
3- (1-oxo-5- (piperidin-4-ylamino) isoindolin-2-yl) piperidine-2, 6-dione was prepared according to the method of scheme 13.
Step 1:
3- (5-amino-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (CAS number 191732-70-4) (2 g,7.71 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (3.1 g,15.43 mmol) were dissolved in dichloromethane (30 mL) at 25 ℃. Acetic acid (10 mL) was added to the reaction solution. The reaction mixture was cooled to 0℃and stirred for 2 hours, and then 2-methylpyridine borane complex (1.64 g,15.43 mmol) was added to the reaction mixture and stirring was continued for 48 hours. The reaction was checked for completion by thin layer chromatography. The reaction was quenched with saturated sodium bicarbonate solution (30 mL), ph=8, and a black solid precipitated. The mixture was filtered, and the filter cake was washed with ethyl acetate, and the solid was collected to give intermediate tert-butyl 4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) amino) piperidine-1-carboxylate (2.4 g, black solid, yield: 70%). 1 H NMR(400MHz,DMSO)δ10.93(s,1H),7.39(d,J＝8.2Hz,1H),6.69(s,2H),6.27(d,J＝7.5Hz,1H),5.02(d,J＝8.8Hz,1H),4.21(dd,J＝51.6,16.5Hz,2H),3.89(d,J＝11.4Hz,2H),3.52(s,2H),2.92(d,J＝12.2Hz,4H),2.59(d,J＝17.2Hz,1H),2.35(d,J＝12.0Hz,1H),1.94–1.77(m,3H),1.41(s,9H).LCMS(ESI)m/z:C 23 H 31 N 4 O 5 + [M+H] + Calculated 443.22; found 443.3.
Step 2:
to a solution of tert-butyl 4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) amino) piperidine-1-carboxylate (2.3 g,3.64 mmol) in dichloromethane (30 mL) was added TFA (10 mL). The reaction solution was stirred at room temperature for 1 hour. LCMS detects completion of the reaction. The reaction solution was concentrated under reduced pressure, and the residue was purified by reverse phase column to give 3- (1-oxo-5- (piperidin-4-ylamino) isoindolin-2-yl) piperidine-2, 6-dione (229 mg, yield: 14%). 1 H NMR(400MHz,DMSO)δ10.93(s,1H),8.70–8.32(m,2H),7.48–7.33(m,1H),6.80–6.61(m,2H),5.02(dd,J＝13.3,5.1Hz,1H),4.22(d,J＝34.3Hz,2H),3.64(t,J＝9.9Hz,1H),3.33(d,J＝12.7Hz,2H),3.03(dd,J＝21.7,11.5Hz,2H),2.95–2.82(m,1H),2.59(d,J＝16.8Hz,1H),2.35(dt,J＝13.2,8.8Hz,1H),2.08(d,J＝13.1Hz,2H),1.99–1.90(m,1H),1.57(dd,J＝21.5,10.5Hz,2H).LC/MS(ESI)m/z:C 18 H 23 N 4 O 3 + [M+H] + Calculated 343.18; found 343.10.
Intermediate example 20: preparation of 2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindoline-5-carboxylic acid (GTC 00260)
To a 250mL one-necked flask was successively added 3- (5-bromo-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (9.0 g,27.851 mmol), palladium acetate (0.19 g,0.836 mmol), ligand Xantphos (16.12 g,27.851 mmol), formic acid (3.85 g,83.553 mmol) and N, N' -dicyclohexylcarbodiimide (1.15 g,5.570 mmol) at room temperature. After stirring the reaction for one minute, triethylamine (7.764 ml,55.702 mmol) was added to the reaction system. The air in the reaction flask was replaced with nitrogen three times, the temperature of the reaction solution was raised to 100℃and the reaction was stirred for 3 hours. TLC detection reaction was complete. The reaction solution was filtered to remove solids, and the filtrate was concentrated to obtain a crude product. The crude product was slurried with dichloromethane, the solid filtered, washed with water and dried in vacuo to give GTC00260 (white solid, 5.96g, yield 74.24%). 1 H NMR(400MHz,DMSO)δ13.33(s,1H),11.01(s,1H),8.17(s,1H),8.08(dd,J＝7.9,1.2Hz,1H),7.83(d,J＝7.9Hz,1H),5.15(dd,J＝13.3,5.1Hz,1H),4.48(dd,J＝50.2,17.7Hz,2H),3.01–2.89(m,1H),2.61(d,J＝16.6Hz,1H),2.41(qd,J＝13.2,4.4Hz,1H),2.03(ddd,J＝10.2,5.2,3.1Hz,1H).LCMS(ESI):C 14 H 13 N 2 O 5 + [M+H] + Calculated values: 289.07; actual measurement value: 289.1.
intermediate example 21: preparation of 2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindoline-5-carboxylic acid (GTC 00923)
1,3 were sequentially added to a 250mL single-necked flask at room temperatureDioxo-1, 3-dihydroisobenzofuran-5-carboxylic acid (9.0 g,46.843 mmol), 3-aminopiperidine-2, 6-dione hydrochloride (6.00 g,46.843 mmol), sodium acetate (11.53 g,140.530 mmol) and 100ml of acetic acid. The reaction mixture was heated to 90℃and stirred for 4 hours. TLC detection reaction was complete. The reaction mixture was concentrated to give crude product. The crude product was slurried with water to precipitate a solid, which was filtered, washed with water and dried in vacuo to give GTC00923 (blue solid, 12.5g, yield 88.29%). 1 H NMR(400MHz,DMSO)δ13.74(s,1H),11.15(s,1H),8.40(dd,J＝7.8,1.4Hz,1H),8.27(d,J＝0.5Hz,1H),8.04(d,J＝7.8Hz,1H),5.20(dd,J＝12.8,5.4Hz,1H),2.99–2.84(m,1H),2.69–2.59(m,1H),2.54(dd,J＝13.3,4.3Hz,1H),2.15–2.03(m,1H).LCMS(ESI):C 14 H 11 N 2 O 6 + [M+H] + Calculated values: 303.05; actual measurement value: 303.1.
intermediate example 22:4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl]Preparation of 2-formic acid (GTC 00948)
4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carboxylic acid was prepared according to the procedure of step 1 of scheme 18.
4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenylbiphenyl was sequentially added to a 500mL single-necked flask at room temperature]A solution of 2-formaldehyde (GTC 00947) (25 g,107.619 mmol) in acetonitrile (100 mL), sodium dihydrogen phosphate (3.36 g,27.981 mmol), water (140 mL), hydrogen peroxide (24.39 g,215.239 mmol) and sodium hypochlorite (13.63 g,150.667 mmol) in water were dissolved and the reaction stirred at room temperature overnight. The reaction was checked for completion by thin layer chromatography. The reaction was washed with water (400 mL), extracted with ethyl acetate (500 mL x 3), and the resulting organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound GTC00948 (white solid, 20g, yield 74.84%). 1 H NMR(400MHz,DMSO)δ12.03(s,1H),7.34–7.00(m,4H),2.35(t,J＝6.4Hz,2H),2.09(s,2H),1.42(t,J＝6.4Hz,2H),0.96(s,6H)。LCMS(ESI):C 17 H 21 FNO 2 + [M+H+CH 3 CN] + Calculated, 290.12, measuredValue 290.1.
Intermediate example 23: (4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl)]Preparation of (2-yl) (piperazin-1-yl) methanone (GTC 00935)
(4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) (piperazin-1-yl) methanone was prepared according to the procedure of step 2 of scheme 18.
Step 2 (1): to a 100mL single vial was added 4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl at room temperature]A solution of 2-carboxylic acid (1.1 g,4.16 mmol) and piperazine-1-carboxylic acid tert-butyl ester (0.85 g,4.57 mmol) in N, N-dimethylformamide (20 mL) was then added to the solution, followed by benzotriazol-1-yl-oxy-tripyrrolidinylphosphine hexafluorophosphate (2.37 g,4.57 mmol) and N, N-diisopropylethylamine (1.61 g,12.46 mmol) in sequence. The atmosphere in the flask was replaced with nitrogen three times and the reaction was stirred at room temperature overnight. The reaction was checked for completion by thin layer chromatography. The reaction solution was washed with water (40 mL), extracted with ethyl acetate (100 ml×3), and the obtained organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1 to 2/1) to give 4- (4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl)]-2-carbonyl) piperazine-1-carboxylic acid tert-butyl ester (colorless oil, 1.4g, yield 85.37%). LCMS (ESI) C 24 H 33 ClN 2 NaO 3 + [M+Na] + Calculated, 455.21, measured, 455.2.
Step 2 (2): to a 100mL single-necked flask was added 4- (4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl) at room temperature]-2-carbonyl) piperazine-1-carboxylic acid tert-butyl ester (1.3 g,3.00 mmol) in ethyl acetate (20 mL), and ethyl acetate solution of hydrochloric acid (40 mL, 3M). The air in the flask was replaced with nitrogen, and the reaction mixture was stirred at room temperature for 3 hours. LC/MS detection reaction was complete. The reaction solution was concentrated under reduced pressure to give compound GTC00935 (white solid, 956mg, yield 95.7%). 1 H NMR(400MHz,DMSO)δ7.38(d,J＝8.4Hz,2H),7.25(d,J＝8.4Hz,2H),3.25(s,1H),3.11(d,J＝38.0Hz,2H),2.88(s,1H),2.53(s,1H),2.47–2.31(m,3H),2.22(s,1H),2.07(d,J＝17.6Hz,1H),1.90(d,J＝17.2Hz,1H),1.78(s,1H),1.43(dd,J＝14.0,6.4Hz,2H),0.98(d,J＝10.4Hz,6H)。LCMS(ESI)C 19 H 26 ClN 2 O + [M+H] + Calculated 333.17, measured 333.2.
Intermediate examples 24 to 62
The following intermediate compounds were prepared according to either scheme 18 or scheme 18 step 2 or the methods of intermediate examples 22-23.
TABLE 2 intermediate examples 24-62 Compounds
Intermediate example 63: n- (4 '-chloro- [1,1' -biphenyl)]Preparation of (2-yl) piperidin-4-amine hydrochloride
N- (4 '-chloro- [1,1' -biphenyl ] -2-yl) piperidin-4-amine hydrochloride was prepared according to the method of scheme 20.
Step 1:
at room temperature, 4 '-chloro- [1,1' -biphenyl]2-amine (480 mg,4.81 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (1150 mg,5.77 mmol) was dissolved in 1, 2-dichloroethane (10 mL). Acetic acid (0.5 mL) was added to the reaction solution, and the reaction solution was stirred for 1 hour. Subsequently, sodium borohydride acetate (2039 mg,9.62 mmol) was added to the solution, and the reaction solution was stirred for an additional 15 hours. LCMS detects completion of the reaction. The reaction was washed with water (50 mL) and extracted with DCM (50 mL. Times.3). The combined organic phases were washed with saturated brine (50 ml×1), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was slurried with petroleum ether/ethyl acetate (5:1, 100 mL) and filtered to give the intermediate product tert-butyl 4- ((4 '-chloro- [1,1' -biphenyl) as a yellow solid ]-2-yl) amino) piperidine-1-carboxylic acid ester (1.9 g, yield: 94%). LCMS (ESI) C 22 H 27 ClN 2 O 2 + [M+H] + Calculated 387.18; found 387.2.
Step 2:
tert-butyl 4- ((4 '-chloro- [1,1' -biphenyl) at room temperature]-2-yl) amino) piperidine-1-carboxylic acid ester (1.9 g,3.83 mmol) was dissolved in dichloromethane and hydrochloric acid/dioxane solution (15 mL, 4M) was added to the solution. The reaction solution was stirred at room temperature for 1 hour. The reaction was checked for completion by thin layer chromatography. The reaction solution was concentrated under reduced pressure, the residue was slurried with petroleum ether/ethyl acetate (5:1, 100 mL), and filtered to give the product N- (4 '-chloro- [1,1' -biphenyl) as a white solid]-2-yl) piperidin-4-amine hydrochloride (500 mg, yield: 45%). 1 H NMR(400MHz,DMSO)δ9.35-8.75(m,2H),7.47(dd,J＝28.8,8.3Hz,4H),7.24(t,J＝7.7Hz,1H),7.04(d,J＝7.4Hz,1H),6.94(d,J＝8.1Hz,1H),6.81(t,J＝7.3Hz,1H),3.59-3.46(m,1H),3.21(d,J＝12.7Hz,2H),2.92(dd,J＝22.1,11.4Hz,2H),1.99(d,J＝11.9Hz,2H),1.59(q,J＝10.0Hz,2H).LCMS(ESI):C 22 H 27 ClN 2 O 2 + [M+H] + Calculated 287.12; found 287.2.
Intermediate example 64: preparation of 4- (chloromethyl) -3- (4-chlorophenyl) pyridine
4- (chloromethyl) -3- (4-chlorophenyl) pyridine was prepared according to the method of scheme 21.
(3- (4-chlorophenyl) pyridin-4-yl) methanol (490 mg,2.23 mmol) was dissolved in dichloromethane (10 mL) at room temperature. The reaction mixture was cooled to zero, and thionyl chloride (1.5 mL,20.68 mmol) was added dropwise. After the addition was completed, the mixture was slowly warmed to room temperature and stirred for 1.5 hours. LCMS detects completion of the reaction. The reaction solution was concentrated under reduced pressure to give 4- (chloromethyl) -3- (4-chlorophenyl) pyridine (415 mg, yield 78.1% as a brown solid). 1 H NMR(400MHz,DMSO)δ8.79(d，J＝4.8Hz，1H)，8.69(s，1H)，7.92(s，1H)，7.59(dd，J＝33.2，8.2Hz，4H)，4.78(s，2H)。LCMS(ESI)C 12 H 9 Cl 2 N + ,[M+H] + Calculated 238.01; found 238.0.
Intermediate example 65: preparation of 1- (2- (5-chloropyridin-2-yl) benzyl) piperazine hydrochloride (GTC 01002)
The method of reference scheme 15 produces 1- (2- (5-chloropyridin-2-yl) benzyl) piperazine hydrochloride.
(2- ((4- (t-Butoxycarbonyl) piperazin-1-yl) methylphenyl) boronic acid (CAS: 1012785-48-6) (300 mg,0.746 mmol), 2-bromo-5-chloropyridine (250 mg,1.299 mmol) were dissolved in ethanol (3 mL), toluene (3 mL) and water (3 mL) at room temperature in a 30mL sealed tube, and tetrakis triphenylphosphine palladium (62.55 mg,0.054 mmol) and sodium carbonate (229.49 mg,2.165 mmol) were added to the solution, air in the reaction flask was purged with nitrogen, the reaction solution was subjected to a microwave reaction at 130℃for 15 minutes, the reaction was detected by thin layer chromatography, the reaction was repeatedly fed three times, the reaction solution was concentrated under reduced pressure, washed with water and extracted with ethyl acetate, and dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (petroleum ether/ethyl acetate=1/0 to 10/1) to give 4- (5-chloropyridine-2-yl) benzyl) piperazine-1-carboxylic acid tert-butyl ester (yellow solid, 12 mg, 1.12% yield (ESI.: S.1%)) 21 H 26 ClN 3 O 2 + [M+H] + Calculated, 388.17, measured, 388.2.
At room temperature, 100mL of the mixture was taken singlyIn the flask was added tert-butyl 4- (2- (5-chloropyridin-2-yl) benzyl) piperazine-1-carboxylate (110 mg,0.284 mmol) and a solution of hydrochloric acid in ethyl acetate (5 mL, 3M) and the reaction mixture was stirred at room temperature for 1 hour. LC/MS detection reaction was complete. The reaction solution was filtered and dried to give compound GTC01002 (white solid, 68mg, yield 73.84%). 1 H NMR(400MHz,MeOD-d4)δ8.92(d,J＝2.0Hz,1H),8.15(dd,J＝8.6,2.4Hz,1H),7.95–7.87(m,2H),7.73(ddd,J＝9.2,8.0,1.2Hz,2H),7.64(td,J＝7.6,1.2Hz,1H),4.55(s,2H),3.75(d,J＝5.2Hz,4H),3.72(d,J＝5.0Hz,4H),2.02(d,J＝3.6Hz,1H)。LCMS(ESI)C 16 H 18 ClN 3 + [M+H] + Calculated 288.12, measured 288.2.
Intermediate examples 66-79
The following intermediate compounds were prepared according to the procedure of scheme 15 or intermediate example 65.
TABLE 3 intermediate examples 66-79 compounds
Intermediate example 80: preparation of 1- ((4, 4-dimethyl-2- (thiophen-2-yl) cyclohex-1-en-1-yl) methyl) piperazine (GTC 00924)
1- ((4, 4-dimethyl-2- (thiophen-2-yl) cyclohex-1-en-1-yl) methyl) piperazine was prepared by the methods of scheme 16, step 1 and scheme 17.
1. Reference to scheme 16 preparation of 4, 4-dimethyl-2- (thiophen-2-yl) cyclohex-1-en-1-carbaldehyde by the method of step 1:
to a 100mL single-necked flask was successively added 2-bromo-4, 4-dimethylcyclohex-1-en-1-carbaldehyde (1.0 g,4.63 mmol), thiophen-2-ylboronic acid (710 mg,5.56 mmol) and carbonic acid at room temperaturePotassium (1.6 g,11.56 mmol), tetrabutylammonium bromide (75 mg,0.232 mmol) and water/chloroform (12 mL, 5:1). Then adding [1,1' -bis (diphenylphosphine) ferrocene into the reaction solution]Palladium (II) dichloride (170 mg,0.232 mmol). The atmosphere in the flask was replaced with nitrogen three times, and the reaction mixture was slowly warmed to 110℃and stirred for 40 minutes. The reaction was checked for completion by thin layer chromatography. The reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1 to 2/1) to give 4, 4-dimethyl-2- (thiophen-2-yl) cyclohex-1-en-1-carbaldehyde (white solid, 660mg, yield 65.8%). LCMS (ESI) C 13 H 16 OS + [M+H] + Calculated, 221.09, found, 221.1.
2. Preparation of 1- ((4, 4-dimethyl-2- (thiophen-2-yl) cyclohex-1-en-1-yl) methyl) piperazine by the method of reference scheme 17:
to a 50mL single-necked flask was added 4, 4-dimethyl-2- (thiophen-2-yl) cyclohex-1-en-1-carbaldehyde (560 mg,2.55 mmol), piperazine-1-carboxylic acid tert-butyl ester (710 mg,3.82 mmol) and dichloroethane (10 mL) in sequence at room temperature. After the reaction mixture was stirred at room temperature for 20 minutes, sodium borohydride acetate (1.08 g,5.09 mmol) was added. The reaction solution was stirred at room temperature for 3 hours. The completion of the reaction was detected by thin layer chromatography, the reaction was quenched with water, the reaction solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1 to 2/1) to give tert-butyl 4- ((4, 4-dimethyl-2- (thiophen-2-yl) cyclohex-1-en-1-yl) methyl) piperazine-1-carboxylate (white solid, 430mg, yield 36.70%). LCMS (ESI) C 22 H 34 N 2 O 2 S + [M+H] + Calculated, 391.23, measured, 391.5.
To a 50mL single vial was added a solution of tert-butyl 4- ((4, 4-dimethyl-2- (thiophen-2-yl) cyclohex-1-en-1-yl) methyl) piperazine-1-carboxylate (430 mg,1.102 mmol) in ethyl acetate (8 mL) followed by an ethyl acetate solution of hydrochloric acid (16 mL, 3M) at room temperature. The reaction solution was stirred at room temperature for 2 hours. LC/MS detection reaction was complete. The reaction mixture was concentrated under reduced pressure to give compound GTC00924 (white solid, 345mg, yield 97%) )。 1 HNMR(400MHz,D2O)δ7.42(d,J＝5.1Hz,1H),7.06–7.01(m,1H),6.87(d,J＝3.4Hz,1H),3.97(s,2H),3.47(d,J＝4.5Hz,4H),3.36(s,4H),2.24–2.14(m,4H),1.45(t,J＝6.2Hz,2H),0.90(s,6H).LCMS(ESI)C 17 H 26 N 2 S + [M+H] + Calculated 291.18, found 291.2.
Intermediate examples 81-91
The following intermediate compounds were prepared according to the procedure for intermediate example 80.
TABLE 4 intermediate examples 81-91 Compounds
Intermediate example 92:1- ((4 '-chloro- [1,1' -biphenyl)]Preparation of (4-yl) methyl) piperazine hydrochloride (GTC 01018)
Reference to the method of scheme 17 produces 1- ((4 '-chloro- [1,1' -biphenyl ] -4-yl) methyl) piperazine hydrochloride.
4 '-chloro- [1,1' -biphenyl was placed in a 100mL single-necked flask at room temperature]4-Formaldehyde (1.1 g,5.09 mmol), piperazine-1-carboxylic acid tert-butyl ester (1.14 g,6.11 mmol) was dissolved in dichloroethane (16 mL), and sodium borohydride acetate (1.62 g,7.64 mmol) was added to the solution in sequence. The reaction solution was stirred at room temperature for 3 hours. The reaction was checked for completion by thin layer chromatography. The reaction was quenched with water (20 mL), extracted with ethyl acetate (20 mL. Times.3), and the resulting organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1 to 2/1) to give 4- ((4 '-chloro- [1,1' -biphenyl)]-4-yl) methyl-piperazine-1-carboxylic acid tert-butyl ester (white solid, 1.4g, yield 71.2%). LCMS (ESI) C 22 H 28 ClN 2 O 2 + [M+H] + Calculated 387.18; found 387.3.
At room temperature, to 100mL single-port bottle Adding 4- ((4 '-chloro- [1,1' -biphenyl)]-4-yl) methyl-piperazine-1-carboxylic acid tert-butyl ester (1.2 g,3.11 mmol) in ethyl acetate (10 mL), and ethyl acetate solution of hydrochloric acid (10 mL,3 m). The reaction solution was stirred at room temperature for 2 hours. LC/MS detection reaction was complete. The reaction solution was concentrated under reduced pressure to give compound GTC01018 (white solid, 1.09g, yield 98.32%). 1 H NMR(400MHz,D 2 O)δ7.71(d,J＝8.2Hz,2H),7.60(t,J＝8.3Hz,4H),7.47(d,J＝8.5Hz,2H),4.52(s,2H),3.65(s,8H).LCMS(ESI)：[M+H] + Calculated 287.12; found 287.2.
Intermediate examples 93-137
The following intermediate compounds were prepared according to the procedure of scheme 17 or intermediate example 92.
TABLE 5 intermediate examples 93-137 compounds
Example 1: preparation of 3- (5- ((4- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03355)
The target product GT-03355 was prepared by reference to the synthetic method of scheme 1.
1- ((4 '-chloro- [1,1' -biphenyl) prepared as intermediate example 3]-2-yl) methyl piperazine (306 mg,0.85 mmol), 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03234) (284 mg,0.85 mmol) in DMF (8 mL) was added TEA (0.56 mL,3.4 mmol) and NaI (128 mg,0.85 mmol) and the reaction stirred at 50℃for 18 h. LCMS detects completion of the reaction. The reaction solution was filtered, and the filtrate was purified by high performance liquid chromatography to give compound GT-03355 as a white solid (349 mg, yield: 75%). 1 H NMR(400MHz,DMSO)δ10.94(s,1H),7.73-7.68(m,2H),7.65-7.55(m,2H),7.45-7.43(m,2H),7.38-7.30(m,4H),7.24-7.20(m,1H),5.08-5.04(m,1H),4.41(d,J＝17.6Hz,1H),4.28(d,J＝17.6Hz,1H),3.26-3.15(m,6H),3.03-2.81(m,5H),2.56-2.50(m,2H),2.37-2.33(m,2H),1.95-1.92(m,1H).LC/MS(ESI)m/z:C 31 H 32 ClN 4 O 3 + [M+H] + Calculated 543.22; actual measurement 543.2.
Example 2: preparation of 3- (5- (4- ((4- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) methyl) phenyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03356)
The target product GT-03356 was prepared by the synthetic method according to scheme 3.
To a solution of 3- (1-oxo-5- (4- (piperazin-1-ylmethyl) phenyl) isoindolin-2-yl) piperidine-2, 6-dione (30 mg,0.066 mmol), 2- (bromomethyl) -4 '-chloro-1, 1' -biphenyl (CAS No. 1001754-57-9) (19 mg,0.066 mmol) prepared according to intermediate 16 in DMF (2 mL) was added TEA (μL,0.2 mmol) and the reaction stirred at 50℃for 2 h. LCMS detects completion of the reaction. The reaction solution was filtered, and the filtrate was purified by high performance liquid chromatography to give compound GT-03356 as a white solid (18 mg, yield: 44%). 1 H NMR(400MHz,MeOD)δ7.81-7.77(m,1H),7.74-7.70(m,1H),7.56-7.49(m,2H),7.39-7.34(m,4H),7.26-7.18(m,5H),6.78-6.74(m,2H),5.11-5.06(m,1H),4.67-4.56(m,2H),4.55-4.48(m,1H),4.24-4.21(m,1H),4.12(s,2H),3.95-3.79(m,2H),3.43-3.30(m,5H),2.99-2.65(m,4H),2.63-2.34(m,2H).LC/MS(ESI)m/z:C 37 H 36 ClN 4 O 3 + [M+H] + Calculated 619.25; found 619.3.
Example 3: preparation of 3- (5- ((1- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) piperidin-4-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03361)
Referring to the procedure of scheme 3, the title compound GT-03361 (17 mg, yield: 40%, white solid) was prepared using 3- (1-oxo-5- (piperidin-4-ylmethyl) isoindolin-2-yl) piperidine-2, 6-dione (GT-3423) and 2- (bromomethyl) -4 '-chloro-1, 1' -biphenyl (CAS number: 1001754-57-9) as starting materials. 1 H NMR(400MHz,MeOD)δ7.86-7.71(m,2H),7.58-7.51(m,4H),7.46-7.32(m,5H),5.17-5.13(m,1H),4.53-4.41(m,3H),4.34(s,2H),3.44-3.37(m,1H),3.35-3.30(m,1H),3.08-2.88(m,2H),2.82-2.78(m,1H),2.71-2.60(m,3H),2.52-2.49(m,1H),2.19-2.16(m,1H),1.92-1.77(m,2H),1.54-1.47(m,1H),1.41-1.38(m,1H).LC/MS(ESI)m/z:C 32 H 33 ClN 3 O 3 + [M+H] + Calculated 542.22; found 542.2.
Example 4: preparation of 3- (5- (4- ((4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) methyl) phenyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03367)
The target product GT-03367 was prepared by the synthetic method according to scheme 4.
To 3- (1-oxo-5- (4- (piperazin-1-ylmethyl) phenyl) isoindolin-2-yl) piperidine-2, 6-dione (30 mg, 66. Mu. Mol) prepared according to intermediate example 16, 4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl]AcOH (1 d) was added to a solution of 2-carbaldehyde (CAS number 1228837-05-5) (20 mg, 79. Mu. Mol) in DMF (2 mL), and the reaction was stirred at 50℃for 17 hours. Subsequently adding NaBH to the reaction solution 3 CN (9 mg,0.13 mmol) and stirring was continued for 2 hours. LCMS detects completion of the reaction. The reaction solution was filtered, and the filtrate was purified by high performance liquid chromatography to give compound GT-03367 (18 mg, yield: 42%) as a white solid. 1 H NMR(400MHz,MeOD)δ7.80-7.75(m,2H),7.72-7.68(m,3H),7.47(d,J＝7.8Hz,2H),7.28(d,J＝8.2Hz,2H),6.98(d,J＝8.2Hz,2H),5.11-5.07(m,1H),4.53-4.42(m,2H),4.16-3.98(m,2H),3.38-3.26(m,3H),3.17-2.86(m,5H),2.86-2.59(m,4H),2.45-2.40(m,1H),2.23-2.17(m,2H),2.14-2.08(m,1H),2.00(brs,2H),1.45(t,J＝6.3Hz,2H),0.91(s,6H).LC/MS(ESI)m/z:C 39 H 44 ClN 4 O 3 + [M+H] + Calculated 651.31; found 651.3.
Example 5: preparation of 3- (5- ((1- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperidin-4-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03368)
Referring to the synthetic method of scheme 4 or the method of example 4, 3- (1-oxo-5- (piperidin-4-ylmethyl) isoindolin-2-yl) piperidine-2, 6-dione (GT-3423) and 4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl were used ]2-Formaldehyde was prepared as a starting material to give the desired product GT-03368 (8 mg, yield: 16%, white solid). 1 H NMR(400MHz,MeOD)δ7.63(d,J＝7.8Hz,1H),7.33-7.27(m,3H),7.24(d,J＝7.8Hz,1H),7.02-6.97(m,2H),5.07-5.02(m,1H),4.41-4.31(m,2H),3.54-3.49(m,2H),3.30-3.26(m,2H),3.03-2.98(m,1H),2.81-2.77(m,1H),2.71(brs,1H),2.63(d,J＝6.4Hz,2H),2.50-2.36(m,3H),2.20-2.13(m,3H),2.12-1.99(m,4H),1.76-1.72(m,2H),1.48(t,J＝6.2Hz,3H),0.92(s,6H).LC/MS(ESI)m/z:C 34 H 41 ClN 3 O 3 + [M+H] + Calculated 574.28; actual measurement 574.3.
Example 6: preparation of 3- (5- (4- ((4- ((4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) methyl) phenyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03453)
The target product GT-03453 was prepared by the synthetic method according to scheme 4.
To 3- (1-oxo-5- (4- (piperazin-1-ylmethyl) phenyl) isoindolin-2-yl) piperidine-2, 6-dione (30 mg, 66. Mu. Mol) prepared according to intermediate example 16, 4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl) prepared according to intermediate example 2]To a solution of 2-carbaldehyde (21 mg, 92. Mu. Mol) in DMF (2 mL) was added DIEA (22. Mu.l, 0.13 mmol), and the reaction was stirred at 50℃for 2 hours. Subsequently adding NaBH to the reaction solution 3 CN (8 mg,0.13 mmol) and stirring was continued for 16 hours. LCMS detects completion of the reaction. Filtering the reaction solution, and using high-efficiency liquid phase for the filtratePurification by chromatography gave compound GT-03453 (10 mg, yield: 14%) as a white solid. 1 H NMR(400MHz,MeOD)δ7.80-7.75(m,2H),7.72-7.68(m,3H),7.49-7.44(m,2H),7.30-7.25(m,2H),7.01-6.96(m,2H),5.11-5.07(m,1H),4.53-4.42(m,2H),4.16-3.98(m,2H),3.38-3.26(m,3H),3.17-2.86(m,5H),2.86-2.59(m,4H),2.45-2.40(m,1H),2.23-2.17(m,2H),2.14-2.08(m,1H),2.00(brs,2H),1.45(t,J＝6.3Hz,2H),0.91(s,6H).LC/MS(ESI)m/z:C 39 H 44 FN 4 O 3 + [M+H] + Calculated 635.34; found 635.3.
Example 7: preparation of 3- (5- ((4- ((4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03454)
Referring to the synthetic method of scheme 4 or the method of example 4, 3- (1-oxo-5- (piperazin-1-ylmethyl) isoindolin-2-yl) piperidine-2, 6-dione prepared according to intermediate example 18 and 4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl prepared according to intermediate example 2 were used]The desired product GT-03454 (6 mg, yield: 12%, white solid) was prepared starting from 2-formaldehyde. 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),7.87–7.77(m,2H),7.75–7.66(m,1H),7.21–7.12(m,4H),5.14(dd,J＝13.2,5.1Hz,1H),4.51–4.33(m,4H),3.48–3.23(m,8H),2.98–2.84(m,2H),2.61(d,J＝16.6Hz,2H),2.43(dd,J＝13.0,4.3Hz,1H),2.35(brs,2H),2.02(s,3H),1.44(t,J＝6.0Hz,2H),0.95(s,6H).LC/MS(ESI)m/z:C 33 H 40 FN 4 O 3 + [M+H] + Calculated 559.31; found 559.3.
Example 7: preparation of 3- (5- ((1- ((4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperidin-4-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03455)
Referring to the synthetic method of scheme 4 or the method of example 4, 3- (1-oxo-5- (piperidin-4-ylmethyl) isoindolin-2-yl) piperidine-2, 6-dione and 4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl prepared according to intermediate example 2 were used]Preparation of the target product GT-03455 (4 mg, yield: 10%, white) from 2-formaldehyde as starting materialColor solids). 1 H NMR(400MHz,MeOD)δ7.75(d,J＝8.0Hz,1H),7.42(s,1H),7.36(d,J＝8.0Hz,1H),7.15-7.12(m,4H),5.19-5.14(m,1H),4.53-4.46(m,2H),3.61(s,2H),3.42-3.39(m,2H),3.18-3.06(m,1H),2.99–2.87(m,1H),2.84-2.81(m,1H),2.76-2.70(m,2H),2.60-2.48(m,3H),2.34-2.23(m,2H),2.23-2.10(m,3H),1.94-1.79(m,2H),1.66-1.46(m,4H),1.04(s,6H).LC/MS(ESI)m/z:C 34 H 41 FN 3 O 3 + [M+H] + Calculated 558.31; found 558.3.
Example 8: preparation of 3- (5- ((4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03468)
The target product GT-03468 was prepared by either the synthetic method of scheme 1 or the method of example 1.
To (2- (2, 6-Dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl methane sulfonate (20 mg,0.054 mmol) prepared according to intermediate example 6, 1- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl)]-2-yl) methyl piperazine (CAS number: 1228780-72-0) (17 mg,0.054 mmol) in DMF (2 mL) was added TEA (18. Mu.L, 0.11 mmol) and the reaction stirred at 50deg.C for 2 hours. LCMS detects completion of the reaction. The reaction solution was filtered, and the filtrate was purified by high performance liquid chromatography to give compound GT-03468 (20 mg, yield: 62%) as a white solid. 1 H NMR(400MHz,DMSO)δ11.03(s,1H),7.64(brs,2H),7.43(d,J＝8.2Hz,2H),7.12(d,J＝8.2Hz,2H),5.16-5.11(m,1H),4.57(d,J＝17.6Hz,1H),4.41(d,J＝17.6Hz,1H),3.79(brs,2H),3.69-3.49(m,4H),3.31-3.19(m,4H),2.96-2.88(m,3H),2.69-2.59(m,3H),2.50-2.40(m,1H),2.30-2.22(m,2H),2.05-1.98(m,3H),1.51-1.42(m,2H),0.96(s,6H).LC/MS(ESI)m/z:C 33 H 39 ClFN 4 O 3 + [M+H] + Calculated 593.27; found 593.3.
Example 9: preparation of 3- (5- ((4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03469)
Reference is made to the synthetic method of scheme 1 or to the method of example 1(2- (2, 6-Dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl methane sulfonate prepared according to intermediate example 8 and 1- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl) were used]-2-yl) methyl piperazine (CAS number: 1228780-72-0) as starting material to give the target product GT-03469 (18 mg, yield: 56%, white solid). 1 H NMR(400MHz,MeOD)δ7.42(s,1H),7.31(d,J＝8.2Hz,2H),7.25(d,J＝10.0Hz,1H),7.01(d,J＝8.2Hz,2H),5.06-5.01(m,1H),4.48-4.37(m,2H),4.06(brs,2H),3.57(brs,2H),3.17-3.06(m,5H),2.86-2.67(m,4H),2.44-2.33(m,1H),2.26-2.23(m3H),2.09-2.03(m,4H),1.50-1.47(m,2H),0.92(s,6H).LC/MS(ESI)m/z:C 33 H 39 ClFN 4 O 3 + [M+H] + Calculated 593.27; found 593.3.
Example 10: preparation of 3- (5- ((3- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-6-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03492)
Referring to the synthetic method of scheme 1 or the method of example 1, (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methylsulfonate prepared according to intermediate example 5 and 3- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl) prepared according to intermediate example 13 were used]-2-yl) methyl) -3, 6-diazabicyclo [3.1.1]Heptane was used as starting material to prepare the desired product GT-03492 (8 mg, yield: 24%, white solid). 1 H NMR(400MHz,MeOD)δ7.81(d,J＝8.0Hz,1H),7.61(s,1H),7.56-7.54(m,1H),7.23-7.20(m,2H),6.96-6.94(m,2H),5.11-5.06(m,1H),4.54-4.44(m,2H),4.32-4.24(m,2H),3.67-3.53(m,1H),2.86-2.64(m,5H),2.47-2.06(m,9H),1.95-1.91(m,3H),1.42(d,J＝6.4Hz,2H),0.91(s,6H).LC/MS(ESI)m/z:C 34 H 40 ClN 4 O 3 + [M+H] + Calculated 587.28; found 587.3.
Example 11: preparation of 3- (5- ((3- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptane-6-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03493)
Referring to the synthetic method of scheme 1 or the method of example 1, (2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl methane sulfonate prepared according to intermediate example 6 and 3- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl) prepared according to intermediate example 13 were used ]-2-yl) methyl) -3, 6-diazabicyclo [3.1.1]Heptane was used as starting material to prepare the desired product GT-03493 (8 mg, yield: 24%, white solid). 1 H NMR(400MHz,MeOD)δ7.66-762(m,2H),7.24-7.22(m,2H),6.97-6.95(m,2H),5.11-5.06(m,1H),4.59-4.47(m,2H),4.38-4.25(m,2H),3.67-3.54(m,1H),3.06-3.03(m,1H),2.93(d,J＝11.9Hz,1H),2.87–2.75(m,2H),2.75–2.64(m,2H),2.44(dd,J＝27.1,14.1Hz,2H),2.25(s,2H),2.19(d,J＝12.5Hz,2H),2.11(s,2H),2.00–1.91(m,2H),1.41(t,J＝6.4Hz,2H),0.91(s,6H).LC/MS(ESI)m/z:C 34 H 39 ClFN 4 O 3 + [M+H] + Calculated 605.27; found 605.3.
Example 12: preparation of 3- (5- ((4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03578)
Referring to the synthetic method of scheme 1 or the method of example 1, (2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl methane sulfonate prepared according to intermediate example 7 and 1- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl) were used]-2-yl) methyl piperazine (CAS number: 1228780-72-0) as starting material to give the target product GT-03578 (36 mg, yield: 45%, white solid). 1 H NMR(400MHz,DMSO)δ11.02(s,1H),7.73(brs,1H),7.60(d,J＝8.6Hz,1H),7.43(d,J＝8.2Hz,2H),7.12(d,J＝8.2Hz,2H),5.16-5.11(m,1H),4.44-4.31(m,2H),4.14-3.75(m,2H),3.69-3.49(m,4H),3.33-3.16(m,4H),2.96-2.88(m,2H),2.68-2.59(m,2H),2.46-2.40(m,1H),2.27(brs,2H),2.02(brs,3H),1.47-1.44(m,2H),1.30-1.23(m,1H),0.96(s,6H).LC/MS(ESI)m/z:C 33 H 39 ClFN 4 O 3 + [M+H] + Calculated 593.27; found 593.3.
Example 13: preparation of 3- (4- ((4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03649)
Referring to the synthetic method of scheme 1 or the method of example 1, (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methylsulfonate and 1- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl) were prepared according to intermediate example 9 ]-2-yl) methyl piperazine (CAS number: 1228780-72-0) as starting material to give the target product GT-03649 (41 mg, yield: 45%, white solid). 1 H NMR(400MHz,DMSO)δ11.04(s,1H),7.79-7.76(m,2H),7.58(t,J＝7.2Hz,1H),7.42(d,J＝8.2Hz,2H),7.12(d,J＝8.2Hz,2H),5.18-5.13(m,1H),4.81-4.68(m,1H),4.47-4.40(m,1H),3.67-3.47(m,4H),3.33-3.17(m,4H),3.01-2.92(m,2H),2.85-2.77(m,2H),2.67-2.62(m,2H),2.41-2.31(m,3H),2.02-1.99(m,3H),1.47-1.44(m,2H),0.96(s,6H).LC/MS(ESI)m/z:C 33 H 40 ClN 4 O 3 + [M+H] + Calculated 575.28; found 575.3.
Example 14: preparation of 3- (5- ((4- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03694)
Referring to the synthetic method of scheme 1 or the method of example 1, (2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl methane sulfonate prepared according to intermediate example 6 and 1- ((4 '-chloro- [1,1' -biphenyl) prepared according to intermediate example 3 were used]-2-yl) methyl piperazine (CAS number: 870812-97-8) as a starting material to give the target product GT-03694 (40 mg, yield: 76%, white solid). 1 H NMR(400MHz,DMSO)δ11.02(s,1H),7.80-7.75(m,1H),7.65-7.63(m,1H),7.52-7.47(m,5H),7.40-7.38(m,2H),7.30-7.28(m,1H),5.16-5.11(m,1H),4.57(d,J＝17.6Hz,1H),4.41(d,J＝17.6Hz,1H),3.33-3.05(m,5H),2.93-2.88(m,3H),2.63-2.58(m,3H),2.42-2.32(m,1H),2.03-1.97(m,2H),1.30-1.23(m,2H).LC/MS(ESI)m/z:C 31 H 31 ClFN 4 O 3 + [M+H] + Calculated 561.21; found 561.2.
Example 15: preparation of 3- (5- ((4- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03695)
Referring to the synthetic method of scheme 1 or the method of example 1, (2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl methane sulfonate prepared according to intermediate example 7 and 1- ((4 '-chloro- [1,1' -biphenyl) were used ]-2-yl) methyl) piperazine as starting material to afford the target product GT-03695 (39 mg, yield: 83%, white solid). 1 H NMR(400MHz,DMSO)δ11.02(s,1H),7.86-7.71(m,1H),7.66-7.58(m,1H),7.56-7.47(m,5H),7.43-7.37(m,2H),7.34-7.25(m,1H),5.14-5.11(m,1H),4.45(d,J＝17.2Hz,2H),4.33(d,J＝17.2Hz,1H),3.31-3.04(m,3H),2.96-2.88(m,2H),2.74-2.58(m,3H),2.44-2.33(m,2H),2.07-1.94(m,2H),1.33-1.23(m,4H).LC/MS(ESI)m/z:C 31 H 31 ClFN 4 O 3 + [M+H] + Calculated 561.21; found 561.2.
Example 16: preparation of 3- (5- ((4- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03696)
Referring to the synthetic method of scheme 1 or the method of example 1, (2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl methane sulfonate prepared according to intermediate example 8 and 1- ((4 '-chloro- [1,1' -biphenyl) were used]-2-yl) methyl) piperazine as starting material to afford the target product GT-03696 (39 mg, yield: 74%, white solid). 1 H NMR(400MHz,DMSO)δ11.01(s,1H),7.98-7.71(m,1H),7.62-7.49(m,4H),7.48-7.43(m,2H),7.41-7.35(m,2H),7.30-7.27(m,1H),5.11-5.07(m,1H),4.49(d,J＝17.6Hz,1H),4.36(d,J＝17.6Hz,1H),4.30-4.05(m,2H),3.33-3.06(m,5H),3.02-2.84(m,3H),2.60-2.58(m,2H),2.46-2.30(m,1H),2.08-1.91(m,1H),1.30-1.24(m,1H).LC/MS(ESI)m/z:C 31 H 31 ClFN 4 O 3 + [M+H] + Calculated 561.21; found 561.2.
Example 17: preparation of 3- (4- ((4- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03876)
Referring to the synthetic method of scheme 1 or the method of example 1, (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methylsulfonate and 1- ((4 '-chloro- [1,1' -biphenyl) prepared according to intermediate example 9 was used]-2-yl) methyl) piperazine as starting material to afford the target product GT-03876 (16 mg, yield: 24%, white solid). 1 H NMR(400MHz,MeOD)δ7.84(d,J＝8.0Hz,1H),7.76-7.70(m,1H),7.68-7.66(m,1H),7.61-7.57(m,1H),7.56-7.51(m,4H),7.42-7.32(m,3H),5.21-5.17(m,1H),4.66-4.53(m,2H),4.27(brs,2H),4.02(brs,2H),3.22-2.88(m,8H),2.87-2.73(m,2H),2.57-2.46(m,1H),2.29-2.12(m,1H).LC/MS(ESI)m/z:C 31 H 32 ClN 4 O 3 + [M+H] + Calculated 543.22; actual measurement 543.2.
Example 18: preparation of 3- (5- ((1- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) piperidin-4-yl) amino) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03877)
Referring to the synthetic method of scheme 1, the target product GT-03877 (30 mg, yield: 52%, white solid) was prepared using 3- (1-oxo-5- (piperidin-4-ylamino) isoindolin-2-yl) piperidine-2, 6-dione prepared according to intermediate example 19 and 2- (bromomethyl) -4 '-chloro-1, 1' -biphenyl (CAS number: 1001754-57-9) as starting materials. 1 H NMR(400MHz,MeOD)δ7.78-7.76(m,1H),7.64-7.48(m,5H),7.44-7.43(m,1H),7.40-7.38(m,2H),6.74-6.71(m,2H),5.10-5.06(m,1H),4.50-4.31(m,4H),3.62-3.57(m,1H),3.44-3.39(m,2H),2.99-2.70(m,4H),2.54-2.38(m,1H),2.26-2.00(m,3H),1.67-1.62(m,2H).LC/MS(ESI)m/z:C 31 H 32 ClN 4 O 3 + [M+H] + Calculated 543.22; actual measurement 543.2.
Example 19: preparation of 3- (5- (3- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) -3, 8-diazabicyclo [3.2.1] oct-8-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03878)
Referring to the synthetic method of scheme 1, 3- (5- (3, 8-diazabicyclo [ 3.2.1) produced according to intermediate example 17 was used]Octane-8-yl) -1-oxo-isoindoline-2-yl piperidine-2, 6-dione and 2- (bromomethyl) -4 '-chloro-1, 1' -biphenyl as starting materialsTarget product GT-03878 (22 mg, yield: 37%, white solid). 1 H NMR(400MHz,MeOD)δ7.73-7.72(m,1H),7.68(d,J＝8.0Hz,1H),7.53-7.44(m,2H),7.42-7.40(m,2H),7.36-7.34(m,1H),7.26-7.24(m,2H),6.92-6.87(m,2H),5.18-5.14(m,1H),4.48-4.41(m,4H),4.33(brs,2H),3.06-2.99(m,2H),2.98-2.77(m,4H),2.58-2.47(m,1H),2.32-2.14(m,3H),2.10-2.00(m,2H).LC/MS(ESI)m/z:C 32 H 32 ClN 4 O 3 + [M+H] + Calculated 555.22; found 555.2.
Example 20: preparation of 3- (5- ((1- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) -3-hydroxyazetidin-3-yl) (hydroxy) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03880)
Referring to the synthetic method of scheme 1, the target product GT-03880 (13 mg, yield: 22%, white solid) was prepared using 3- (5- (hydroxy (3-hydroxyazetidin-3-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione and 2- (bromomethyl) -4 '-chloro-1, 1' -biphenyl (CAS number: 1001754-57-9) prepared according to intermediate example 15 as starting materials. 1 H NMR(400MHz,MeOD)δ7.78(dd,J＝8.0,1.6Hz,1H),7.67-7.52(m,6H),7.46-7.34(m,4H),5.20-5.15(m,1H),4.77-4.68(m,1H),4.59-4.42(m,5H),4.37-4.21(m,1H),4.09-3.85(m,1H),3.60-3.46(m,1H),3.01-2.86(m,1H),2.83-2.73(m,1H),2.52-2.50(m,1H),2.28-2.08(m,1H).LC/MS(ESI)m/z:C 30 H 29 ClN 3 O 5 + [M+H] + Calculated 546.18; found 546.2.
Example 21: preparation of 3- (5- ((1- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) azetidin-3-ylidene) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03881)
Referring to the procedure of scheme 1, the desired product GT-03881 (11 mg, yield: 20%, white solid) was prepared using 3- (5- (azetidin-3-ylmethylene) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione prepared according to intermediate example 13 and 2- (bromomethyl) -4 '-chloro-1, 1' -biphenyl (CAS number: 1001754-57-9) as starting materials. 1 H NMR(400MHz,MeOD)δ7.81(d,J＝8.0Hz,1H),7.63-7.54(m,3H),7.49(d,J＝8.4Hz,2H),7.45-7.42(m,1H),7.39(d,J＝8.4Hz,2H),7.32(s,1H),7.25(d,J＝8.0Hz,1H),6.60(s,1H),5.20-5.16(m,1H),4.95-4.88(m,2H),4.64(s,2H),4.57-4.47(m,2H),2.99-2.88(m,1H),2.84-2.78(m,1H),2.59-2.45(m,1H),2.24-2.17(m,1H).LC/MS(ESI)m/z:C 30 H 27 ClN 3 O 3 + [M+H] + Calculated 512.17; found 512.2.
Example 22: preparation of 3- (5- (((1R, 4R) -5- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03887)
Referring to the synthetic method of scheme 1 or the method of example 1, (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methylsulfonate and (1R, 4R) -2- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl) prepared according to intermediate example 5 were used]-2-yl) methyl) -2, 5-diazabicyclo [2.2.1]Heptane was used as a starting material to give the desired product GT-03887 (42 mg, yield: 63%, white solid). 1 H NMR(400MHz,MeOD)δ7.89(d,J＝8.0Hz,1H),7.82-7.75(m,1H),7.70-7.63(m,1H),7.44(d,J＝8.4Hz,2H),7.17(d,J＝8.4Hz,2H),5.22-5.17(m,1H),5.04-4.93(m,4H),4.64-4.50(m,2H),4.33-4.19(m,2H),3.86-3.83(m,1H),3.76-3.70(m,1H),3.50-3.40(m,3H),3.02-2.88(m,1H),2.83-2.79(m,1H),2.61-2.47(m,1H),2.46-2.29(m,3H),2.23-2.17m,3H),1.61(t,J＝6.4Hz,2H),1.05(s,6H).LC/MS(ESI)m/z:C 34 H 40 ClN 4 O 3 + [M+H] + Calculated 587.28; found 587.3.
Example 23: preparation of 3- (5- (((1R, 4R) -5- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03888)
Referring to the synthetic method of scheme 1 or the method of example 1, (2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl methane sulfonate prepared according to intermediate example 6 and (1R, 4R) -2- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl) were used]-2-yl) methyl) -2, 5-diazabicyclo [2.2.1]Heptane as starting materialTo the target product GT-03888 (43 mg, yield: 66%, white solid). 1 H NMR(400MHz,MeOD)δ7.83-7.71(m,2H),7.45(d,J＝8.4Hz,2H),7.18(d,J＝8.4Hz,2H),5.21-5.17m,1H),5.04-4.97(m,2H),4.67-4.49(m,2H),4.34-4.27(m,3H),4.16-4.05(m,1H),3.86-3.83(m,1H),3.76-3.70(m,1H),3.51-3.36(m,3H),3.00-2.88(m,1H),2.83-2.79(m,1H),2.59-2.50(m,1H),2.44-2.28(m,3H),2.22-2.17(m,3H),1.61(t,J＝6.4Hz,2H),1.05(s,6H).LC/MS(ESI)m/z:C 34 H 39 ClFN 4 O 3 + [M+H] + Calculated 605.27; found 605.3.
Example 24: preparation of 3- (5- ((3- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -3, 8-diazabicyclo [3.2.1] octane-8-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03889)
Referring to the synthetic method of scheme 1 or the method of example 1, (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methylsulfonate prepared according to intermediate example 5 and 3- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl) prepared according to intermediate example 93 were used]-2-yl) methyl) -3, 8-diazabicyclo [3.2.1]Octane was prepared as a starting material to give the objective product GT-03889 (26 mg, yield: 38%, white solid). 1 H NMR(400MHz,MeOD)δ7.80(d,J＝8.0Hz,1H),7.66(s,1H),7.57(d,J＝8.0Hz,1H),7.25-7.19(m,2H),6.97-6.92(m,2H),5.11-5.06(m,1H),4.57-4.35(m,2H),4.22(brs,2H),3.80(brs,2H),2.87-2.64(m,6H),2.52-2.35(m,1H),2.30-2.18(m,9H),1.93(brs,2H),1.42-1.39(m,2H),0.90(s,6H).LC/MS(ESI)m/z:C 35 H 42 ClN 4 O 3 + [M+H] + Calculated 601.29; found 601.3.
Example 25: preparation of 3- (5- ((3- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -3, 8-diazabicyclo [3.2.1] octane-8-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03890)
Referring to the synthetic method of scheme 1 or the method of example 1, (2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methylsulfonic acid prepared according to intermediate example 6 was usedEsters and 3- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl) prepared according to intermediate example 93 ]-2-yl) methyl) -3, 8-diazabicyclo [3.2.1]Octane was prepared as a starting material to give the objective product GT-03890 (21 mg, yield: 31%, white solid). 1 H NMR(400MHz,MeOD)δ7.71-7.61(m,2H),7.21(d,J＝8.4Hz,2H),6.94(d,J＝8.4Hz,2H),5.10-5.06(m,1H),4.52(q,J＝17.6Hz,2H),4.29(brs,2H),3.92(brs,2H),3.00-2.91(m,2H),2.88-2.77(m,3H),2.74-2.66(m,1H),2.45-2.42(m,2H),2.37-2.25(m,3H),2.21-2.17(m,2H),2.16-2.06(m,3H),1.95(brs,2H),1.42(t,J＝6.6Hz,2H),0.9(s,6H).LC/MS(ESI)m/z:C 35 H 41 ClFN 4 O 3 + [M+H] + Calculated 619.28; found 619.3.
Example 26: preparation of 3- (5- ((4- (4 '-chloro- [1,1' -biphenyl ] -2-carbonyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03891)
The target product GT-03891 was prepared by the synthetic method according to scheme 6.
To 3- (1-oxo-5- (piperazin-1-ylmethyl) isoindolin-2-yl) piperidine-2, 6-dione (45 mg,0.13 mmol) prepared according to intermediate example 18, 4 '-chloro- [1,1' -biphenyl]To a solution of 2-carboxylic acid (CAS number 7079-15-4) (40 mg,0.17 mmol) in DMF (2 mL) was added TEA (55. Mu.L, 0.39 mmol) and HATU (75 mg,0.19 mmol). The reaction solution was stirred at 50℃for 2 hours. LCMS detects completion of the reaction. The reaction solution was filtered, and the filtrate was purified by high performance liquid chromatography to give compound GT-03891 (26 mg, yield: 35%) as a white solid. 1 H NMR(400MHz,MeOD)δ7.92(d,J＝7.6Hz,1H),7.71(s,1H),7.65-7.58(m,2H),7.56-7.46(m,7H),5.21-5.17(m,1H),5.02-4.92(m,3H),4.57(q,J＝17.2Hz,2H),4.39-4.35(m,2H),3.51-3.40(m,4H),3.13-3.03(m,1H),2.97-2.92(m,1H),2.86-2.77(m,1H),2.61-2.47(m,1H),2.29-2.14(m,1H).LC/MS(ESI)m/z:C 31 H 30 ClN 4 O 4 + [M+H] + Calculated 557.20; found 557.2.
Example 27: preparation of 3- (5- ((4- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) amino) piperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03991)
Synthetic method or according to scheme 1The procedure of example 1 was followed using 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03234) and N- (4 '-chloro- [1,1' -biphenyl) prepared according to intermediate example 63 ]-2-yl) piperidin-4-amine hydrochloride as starting material gave the target product GT-03991 (17 mg, yield: 24%). 1 H NMR(400MHz,MeOD)δ7.92(d,J＝8.0Hz,1H),7.82(s,1H),7.71(d,J＝8.0Hz,1H),7.50(d,J＝8.0Hz,2H),7.40(d,J＝8.0Hz,2H),7.35-7.31(m,1H),7.15(d,J＝8.0Hz,1H),7.06(d,J＝8.0Hz,1H),7.00(t,J＝8.0Hz,1H),5.22-5.17(m,1H),4.64-4.53(m,2H),4.47(s,2H),3.68-3.62(m,1H),3.57-3.54(m,2H),3.17(t,J＝12.4Hz,2H),2.94-2.89(m,1H),2.86-2.73(m,1H),2.59-2.51(m,1H),2.25-2.19(m,3H),1.75-1.67(m,2H).LC/MS(ESI)m/z:C 31 H 32 ClN 4 O 3 + [M+H] + Calculated 543.22; actual measurement 543.2.
Example 28: preparation of 3- (5- ((1- (4 '-chloro- [1,1' -biphenyl ] -2-carbonyl) azetidin-3-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03922)
Referring to the synthetic method of scheme 6, 3- (5- (azetidin-3-ylmethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione and 4 '-chloro- [1,1' -biphenyl prepared according to intermediate example 14 were used]2-Carboxylic acid (CAS number: 7079-15-4) was used as a starting material to prepare the target product GT-03922 (35 mg, yield: 57%, white solid). 1 H NMR(400MHz,MeOD)δ7.60(d,J＝7.6Hz,1H),7.47-7.26(m,8H),7.17(s,1H),7.11(d,J＝7.6Hz,1H),5.07-5.01(m,1H),4.43-4.29(m,2H),3.99-3.88(m,1H),3.59-3.55(m,1H),3.53-3.45(m,1H),3.08-3.04(m,1H),2.87-2.76(m,1H),2.74-2.63(m,2H),2.58-2.52(m,2H),2.46-2.30(m,1H),2.11-2.01(m,1H).LC/MS(ESI)m/z:C 30 H 27 ClN 3 O 4 + [M+H] + Calculated 528.17; found 528.2.
Example 29: preparation of 3- (5- ((1- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) azetidin-3-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03923)
Referring to the synthetic method of scheme 2, 3- (5- (azetidin-3-ylmethyl) -1-oxoisoindole prepared according to intermediate example 14 was usedIn-2-yl) piperidine-2, 6-dione and 2- (bromomethyl) -4 '-chloro-1, 1' -biphenyl (CAS no: 1001754-57-9) as starting material to give the target product GT-03923 (38 mg, yield: 63%, white solid). 1 H NMR(400MHz,MeOD)δ7.65-7.63(m,1H),7.47-7.39(m,5H),7.31-7.18(m,3H),7.12(d,J＝7.6Hz,1H),5.08-5.02(m,1H),4.74-4.69(m,3H),4.46-4.34(m,2H),4.32(s,1H),3.96-3.91(m,1H),3.83-3.80(m,1H),3.58-3.53(m,1H),3.06-2.99(m,1H),2.85-2.75(m,2H),2.74-2.64(m,1H),2.41-2.34(m,1H),2.14-2.00(m,1H).LC/MS(ESI)m/z:C 30 H 29 ClN 3 O 3 + [M+H] + Calculated 514.19; actual measurement 514.2.
Example 30: preparation of 3- (5- ((6- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03995)
Referring to the synthetic method of scheme 1 or the method of example 1, (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methylsulfonate prepared according to intermediate example 5 and 6- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl) prepared according to intermediate example 14 were used]-2-yl) methyl) -3, 6-diazabicyclo [3.1.1]Heptane was used as a starting material to prepare the desired product GT-03995 (8 mg, yield: 12%, white solid). 1 H NMR(400MHz,MeOD)δ7.82(d,J＝8.0Hz,1H),7.68(s,1H),7.58(d,J＝8.0Hz,1H),7.25-7.19(m,2H),6.97-6.92(m,2H),5.12-5.07(m,1H),4.58-4.37(m,2H),3.80(brs,2H),2.88-2.65(m,6H),2.54-2.37(m,1H),2.31-2.19(m,9H),1.95-1.90(m,2H),1.42-1.39(m,2H),0.90(s,6H).LC/MS(ESI)m/z:C 34 H 40 ClN 4 O 3 + [M+H] + Calculated 587.28; found 587.3.
Example 31: preparation of 3- (5- ((8- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -3, 8-diazabicyclo [3.2.1] octane-3-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03996)
Referring to the synthetic method of scheme 1 or the method of example 1, (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl was usedMethane sulfonate and 8- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl) prepared according to intermediate example 94 ]-2-yl) methyl) -3, 8-diazabicyclo [3.2.1]Octane was prepared as a starting material to give the objective product GT-03996 (32 mg, yield: 42%, white solid). 1 H NMR(400MHz,MeOD)δ7.67(d,J＝8.0Hz,1H),7.46(s,1H),7.40(d,J＝8.0Hz,1H),7.32(d,J＝8.0Hz,2H),7.07(d,J＝8.0Hz,2H),5.08-5.03(m,1H),4.47-4.27(m,2H),3.67(brs,4H),3.52(brs,2H),2.89-2.73(m,3H),2.72-2.70(m,1H),2.69-2.55(m,2H),2.43-2.35(m,1H),2.25-2.20(m,2H),2.13-2.02(m,3H),1.90-1.84(m,2H),1.49(t,J＝8.0Hz,2H),1.33-1.24(m,2H),0.93(s,6H).LC/MS(ESI)m/z:C 35 H 42 ClN 4 O 3 + [M+H] + Calculated 601.29; found 601.3.
Example 32: preparation of 3- (5- (((1R, 5S) -6- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-06194)
The target product GT-06194 (8 mg, yield: 12%, white solid) was obtained by referring to the synthetic method of scheme 1 or the method of example 1. 1 H NMR(400MHz,MeOD)δ7.82(d,J＝8.0Hz,1H),7.68(s,1H),7.58(d,J＝8.0Hz,1H),7.25-7.19(m,2H),6.97-6.92(m,2H),5.12-5.07(m,1H),4.58-4.37(m,2H),3.80(brs,2H),2.88-2.65(m,6H),2.54-2.37(m,1H),2.31-2.19(m,9H),1.95-1.90(m,2H),1.42-1.39(m,2H),0.90(s,6H).LC/MS(ESI)m/z:C 34 H 40 ClN 4 O 3 + [M+H] + Calculated 587.28; found 587.3.
Example 33: preparation of 3- (5- (((1S, 4S) -5- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03997)
The desired product GT-03997 (36 mg, yield: 48%, white solid) was obtained by referring to the synthetic method of scheme 1 or the method of example 1. 1 H NMR(400MHz,MeOD)δ7.89(d,J＝8.0Hz,1H),7.82-7.77(m,1H),7.72-7.64(m,1H),7.44(d,J＝8.0Hz,2H),7.18(d,J＝8.0Hz,2H),5.22-5.17(m,1H),4.62-4.51(m,2H),4.44-4.16(m,2H),3.91-3.68(m,2H),2.99-2.87(m,1H),2.83-2.77(m,1H),2.58-2.49(m,1H),2.42-2.39(m,2H),2.26-2.10(m,3H),1.61(t,J＝6.4Hz,2H),1.05(s,6H).LC/MS(ESI)m/z:C 34 H 40 ClN 4 O 3 + [M+H] + Calculated 587.28; found 587.3.
Example 34: preparation of 3- (5- ((4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-02785)
Referring to the synthetic method of scheme 1, (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl methanesulfonate and 1- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl) prepared according to intermediate example 5 was used]-2-yl) methyl piperazine (CAS number: 1228780-72-0) as starting material to give the target product GT-02785 (20 mg, yield: 62%, white solid). 1 H NMR(400MHz,MeOD)δ7.87(d,J＝7.8Hz,1H),7.73(s,1H),7.63(d,J＝7.8Hz,1H),7.42(d,J＝8.4Hz,2H),7.12(d,J＝8.4Hz,2H),5.21-5.16(m,1H),4.60-4.49(m,2H),4.22(brs,2H),3.61(brs,2H),3.32-3.28(m,2H),3.26–3,12(m,5H),3.02-2.87(m,2H),2.87-2.76(m,1H),2.52–2.42(m,1H),2.38–2.32(m,2H),2.25-2.16(m,1H),2.14(s,2H),1.59(t,J＝6.4Hz,2H),1.04(s,6H).LC/MS(ESI)m/z:C 33 H 40 ClN 4 O 3 + [M+H] + Calculated 575.28; found 575.3.
Example 35: preparation of 3- (5- ((4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) amino) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-04252)
Referring to the synthetic method of scheme 4, 3- (1-oxo-5- (piperazin-1-ylamino) isoindolin-2-yl) piperidine-2, 6-dione and 4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl prepared according to intermediate example 11 were used]2-Formaldehyde (CAS number 1228837-05-5) was used as starting material to prepare the target product GT-04252 (15 mg, yield: 17%, white solid). 1 H NMR(400MHz,MeOD)δ7.44(d,J＝8.4Hz,1H),7.39-7.33(m,2H),7.09-7.02(m,2H),6.90(s,1H),6.81(dd,J＝8.4,1.8Hz,1H),5.00-4.95(m,1H),4.35-4.16(m,2H),3.62(s,2H),3.46-3.29(m,2H),3.10-2.95(m,2H),2.90-2.75(m,6H),2.72-2.60(m,1H),2.40-2.29(m,1H),2.21-2.18(m,2H),2.05(brs,3H),1.51(t,J＝6.4Hz,2H),0.94(s,6H).LC/MS(ESI)m/z:C 32 H 39 ClN 5 O 3 + [M+H] + Calculated 576.27; found 576.3.
Example 36: preparation of 3- (5- ((5- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -2, 5-diazabicyclo [2.2.2] octane-2-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-0467)
Referring to the synthetic method of scheme 1, (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl methanesulfonate and 2- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl) prepared according to intermediate example 5 was used]-2-yl) methyl) -2, 5-diazabicyclo [2.2.2]Octane (GTC 00247) was used as starting material to prepare the target product GT-0467 (29 mg, yield: 42%, white solid). 1 H NMR(400MHz,MeOD)δ7.78(d,J＝7.8Hz,1H),7.69-7.45(m,2H),7.34(d,J＝7.4Hz,2H),7.08(d,J＝7.4Hz,2H),5.11-5.05(m,1H),4.53-4.37(m,2H),4.21-4.01(m,4H),3.88-3.72(m,2H),3.61-3.32(m,2H),2.87-2.78(m,1H),2.75-2.61(m,1H),2.48-2.37(m,1H),2.32-2.18(m,3H),2.15-1.96(m,3H),1.96-1.62(m,2H),1.49(t,J＝6.4Hz,2H),0.93(s,6H).LC/MS(ESI)m/z:C 35 H 42 ClFN 4 O 3 + [M+H] + Calculated 601.29; found 601.3.
Example 37: preparation of 3- (5- ((5- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -2, 5-diazabicyclo [2.2.2] octane-2-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-04168)
Referring to the synthetic method of scheme 1, (2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl methanesulfonate and 2- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl) prepared according to intermediate example 6 was used]-2-yl) methyl) -2, 5-diazabicyclo [2.2.2]Octane was prepared as a starting material to give the objective product GT-04168 (26 mg, yield: 37%, white solid). 1 H NMR(400MHz,MeOD)δ7.61(d,J＝6.4Hz,1H),7.56-7.49(m,1H),7.34(d,J＝8.4Hz,2H),7.08(d,J＝8.4Hz,2H),5.11-5.06(m,1H),4.57-4.44(m,2H),4.38-3.98(m,4H),3.91-3.72(m,2H),3.59-3.33(m,3H),2.90-2.76(m,1H),2.73-2.71(m,1H),2.45-2.27(m,1H),2.27(brs,2H),2.21-1.96(m,6H),1.94-1.6(m,2H),1.49(t,J＝6.5Hz,2H),0.93(s,6H).LC/MS(ESI)m/z:C 35 H 41 ClFN 4 O 3 + [M+H] + Calculated 619.28; found 619.3.
Example 38: preparation of 3- (5- ((4- (4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-04224)
Referring to the synthetic method of scheme 6, 3- (1-oxo-5- (piperazin-1-ylmethyl) isoindolin-2-yl) piperidine-2, 6-dione and 4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl prepared according to intermediate example 18 were used]2-formic acid (CAS number 2716235-85-5) as starting material gave the target product GT-04224 (27 mg, yield: 43%, white solid). 1 H NMR(400MHz,MeOD)δ7.93(d,J＝7.8Hz,1H),7.70(s,1H),7.61(d,J＝7.8Hz,1H),7.47-7.34(m,2H),7.27-7.21(m,2H),5.22-5.18(m,1H),4.69-4.50(m,2H),4.36(brs,2H),3.16-3.10(m,4H),3.04-2.88(m,2H),2.87-2.73(m,2H),2.62-2.45(m,4H),2.34-2.11(m,2H),2.05-1.97(m,1H),1.59-1.55(m,2H),1.06(s,6H).LC/MS(ESI)m/z:C 33 H 38 ClN 4 O 4 + [M+H] + Calculated 589.26; found 589.3.
Example 39: preparation of 3- (5- ((4- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) amino) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-04196)
Referring to the synthetic method of scheme 2, the target product GT-04196 (34 mg, yield: 56%, white solid) was prepared using 3- (1-oxo-5- (piperazin-1-ylamino) isoindolin-2-yl) piperidine-2, 6-dione prepared according to intermediate example 11 and 2- (bromomethyl) -4 '-chloro-1, 1' -biphenyl (CAS number: 1001754-57-9) as starting materials. 1 H NMR(400MHz,MeOD)δ7.71-7.63(m,1H),7.53-7.40(m,5H),7.35-7.23(m,3H),6.88(s,1H),6.78(dd,J＝8.4,1.8Hz,1H),5.02-4.95(m,1H),4.36(s,2H),4.31-4.16(m,2H),3.31-3.27(m,2H),3.08-2.86(m,4H),2.86-2.60(m,4H),2.40-2.21(m,1H),2.09-1.92(m,1H).LC/MS(ESI)m/z:C 30 H 31 ClN 5 O 3 + [M+H] + Calculated 544.21; found 544.2.
Example 40: preparation of 3- (5- ((1- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) azetidin-3-yl) amino) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-04204)
Referring to the synthetic method of scheme 2, the target product GT-04204 (10 mg, yield: 19%, white solid) was prepared using 3- (5- (azetidin-3-ylamino) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione and 2- (bromomethyl) -4 '-chloro-1, 1' -biphenyl (CAS number: 1001754-57-9) prepared according to intermediate example 12 as starting materials. 1 H NMR(400MHz,MeOD)δ7.54-7.33(m,5H),7.35-7.25(m,4H),6.59-6.39(m,1H),5.01-4.96(m,1H),4.47(s,2H),4.44-4.29(m,3H),4.24(t,J＝11.2Hz,2H),3.87-3.59(m,2H),2.84-2.76(m,1H),2.70-2.64(m,1H),2.40-2.21(m,1H),2.12-1.92(m,1H).LC/MS(ESI)m/z:C 29 H 27 ClFN 4 O 3 + [M+H] + Calculated 533.18; found 533.2.
Example 41: preparation of 3- (5- ((4- ((3- (4-chlorophenyl) pyridin-4-yl) methyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-04275)
Referring to the synthetic method of scheme 2, the title product GT-04275 (36 mg, yield: 49%) was prepared using 3- (1-oxo-5- (piperazin-1-ylmethyl) isoindolin-2-yl) piperidine-2, 6-dione and 4- (chloromethyl) -3- (4-chlorophenyl) pyridine prepared according to intermediate example 64 as starting materials. 1 H NMR(400MHz,MeOD)δ8.89(d,J＝6.0Hz,1H),8.81(s,1H),8.47(d,J＝6.0Hz,1H),7.91(d,J＝7.8Hz,1H),7.88(s,1H),7.75(d,J＝7.8Hz,1H),7.64-7.57(m,2H),7.54-7.48(m,2H),5.21-5.17(m,1H),4.59(d,J＝10.0Hz,2H),4.55(s,2H),3.93(s,2H),3.40(brs,4H),2.97-2.78(m,4H),2.71(brs,1H),2.59-2.48(m,1H),2.27-2.11(m,1H).LC/MS(ESI)m/z:C 30 H 31 ClN 5 O 3 + [M+H] + Calculated 544.21; found 544.2.
Example 42: preparation of 3- (5- ((4- (3- (4-chlorophenyl) isonicotinyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-04222)
Referring to the synthetic method of scheme 6, the target product GT-04222 (23 mg, yield: 36%, white solid) was prepared using 3- (1-oxo-5- (piperazin-1-ylmethyl) isoindolin-2-yl) piperidine-2, 6-dione prepared according to intermediate example 18 and 3- (4-chlorophenyl) isonicotinic acid (CAS number: 883107-39-9) as starting materials. 1 H NMR(400MHz,MeOD)δ8.75(s,1H),8.69(d,J＝5.6Hz,1H),7.78(d,J＝5.6Hz,1H),7.70(d,J＝7.8Hz,1H),7.58(s,1H),7.45(d,J＝7.8Hz,1H),7.40(d,J＝8.0Hz,2H),7.33(d,J＝8.0Hz,2H),5.01-4.95(m,1H),4.37(q,J＝17.2Hz,2H),4.24(s,2H),3.43-3.26(m,2H),3.26-3.12(m,3H),3.06-2.96(m,2H),2.77-2.68(m,2H),2.63-2.57(m,1H),2.36-2.27(m,1H),2.07-1.91(m,1H).LC/MS(ESI)m/z:C 30 H 29 ClN 5 O 4 + [M+H] + Calculated 558.19; found 558.2.
Example 43: preparation of 3- (5- ((4- ((4 '-fluoro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-04256)
Referring to the synthetic method of scheme 2, the target product GT-04256 (28 mg, yield: 44%, white solid) was prepared using 3- (1-oxo-5- (piperazin-1-ylmethyl) isoindolin-2-yl) piperidine-2, 6-dione and 2- (bromomethyl) -4 '-chloro-1, 1' -biphenyl (CAS number: 1001754-57-9) prepared according to intermediate example 18 as starting materials. 1 H NMR(400MHz,MeOD)δ7.75(d,J＝7.8Hz,1H),7.58-7.54(m,2H),7.49(d,J＝8.0Hz,1H),7.39-7.36(m,2H),7.29-7.22(m,3H),7.11(t,J＝8.8Hz,2H),5.09-5.04(m,1H),4.51-4.33(m,2H),4.10(brs,2H),3.97(brs,1H),3.03(brs,4H),2.92-2.64(m,6H),2.46-2.35(m,1H),2.16-1.97(m,1H).LC/MS(ESI)m/z:C 31 H 32 FN 4 O 3 + [M+H] + Calculated 527.25; found 527.3.
Example 44: preparation of 3- (5- ((4- (4 '-fluoro- [1,1' -biphenyl ] -2-carbonyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-04194)
Reference toScheme 6 Synthesis of method using 3- (1-oxo-5- (piperazin-1-ylmethyl) isoindolin-2-yl) piperidine-2, 6-dione and 4 '-fluoro- [1,1' -biphenyl) prepared according to intermediate example 18]2-formic acid (CAS number 1841-57-2) as starting material gave the target product GT-04194 (10 mg, yield: 16%, white solid). 1 H NMR(400MHz,MeOD)δ7.92(d,J＝7.8Hz,1H),7.72(s,1H),7.65-7.57(m,2H),7.57-7.41(m,5H),7.21-7.19(m,2H),5.21-5.19(m,1H),4.58(q,J＝17.2Hz,2H),4.41(brs,2H),3.59-3.33(m,4H),3.15-3.08(m,2H),3.02-2.88(m,2H),2.87-2.75(m,2H),2.57-2.43(m,1H),2.29-2.13(m,1H).LC/MS(ESI)m/z:C 31 H 30 FN 4 O 4 + [M+H] + Calculated 541.22; found 541.3.
Example 45: preparation of 3- (5- ((4- ((4 '-fluoro-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-04193)
Referring to the synthetic method of scheme 1, (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl methane sulfonate prepared according to intermediate example 5 and 1- ((4 '-fluoro-3, 4,5, 6-tetrahydro- [1,1' -biphenyl) were used ]-2-yl) methyl) piperazine as starting material to afford the target product GT-04193 (30 mg, yield: 46%, white solid). 1 H NMR(400MHz,MeOD)δ7.89(d,J＝7.8Hz,1H),7.78(s,1H),7.67(d,J＝7.8Hz,1H),7.24-7.07(m,4H),5.21-5.17(m,1H),4.56(q,J＝17.2Hz,2H),4.36(brs,2H),3.68(brs,2H),3.39(brs,8H),3.00-2.87(m,1H),2.86-2.72(m,1H),2.61-2.42(m,1H),2.37-2.34(m,4H),2.27-2.12(m,1H),1.82(s,4H).LC/MS(ESI)m/z:C 31 H 36 FN 4 O 3 + [M+H] + Calculated 531.28; actual measurement 531.3.
Example 46: preparation of 3- (5- ((4- (4 '-fluoro-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-04170)
Referring to the synthetic method of scheme 1, (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl methanesulfonate prepared according to intermediate example 5 and (4 '-fluoro-3, 4,5, 6-tetrahydro- [1,1' -biphenyl) prepared according to intermediate example 24 were used]-2-yl) (piperazin-1-yl) methanone as starting material gave the target product GT-04170 (42 mg, yield: 63%, white solid). 1 H NMR(400MHz,MeOD)δ7.91(d,J＝7.6Hz,1H),7.74(brs,1H),7.63(brs,1H),7.32-7.23(m,2H),7.17-7.00(m,2H),5.30-5.12(m,1H),4.69-4.51(m,3H),4.35-4.20(m,2H),4.15-3.79(m,1H),3.51-3.41(m,2H),3.27-3.03(m,2H),2.99-2.91(m,1H),2.87-2.77(m,1H),2.76-2.61(m,2H),2.61-2.43(m,2H),2.29-2.09(m,3H),1.95-1.60(m,4H).LC/MS(ESI)m/z:C 31 H 34 FN 4 O 4 + [M+H] + Calculated 545.26; found 545.3.
Example 47: preparation of 3- (5- ((3- (4 '-fluoro-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) -3, 6-diazabicyclo [3.1.1] heptan-6-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-0469)
Referring to the synthetic procedure of scheme 1, (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl methanesulfonate prepared according to intermediate example 5 and (3, 6-diazabicyclo [ 3.1.1) prepared according to intermediate example 25 were used ]Heptane-3-yl) (4 '-fluoro-3, 4,5, 6-tetrahydro- [1,1' -biphenyl]-2-yl) methanone as starting material gave the target product GT-0469 (37 mg, yield: 54%, white solid). 1 H NMR(400MHz,MeOD)δ7.87(d,J＝7.8Hz,1H),7.79(s,1H),7.70-7.65(m,1H),7.41-7.23(m,2H),7.12-7.05(m,2H),5.21-5.16(m,1H),4.71(s,1H),4.66-4.50(m,2H),4.46-4.37(m,1H),4.35-4.18(m,1H),4.02-3.96(m,1H),3.80-3.71(m,2H),3.23-3.04(m,1H),3.02-2.87(m,1H),2.87-2.76(m,1H),2.71-2.65(m,1H),2.57-2.52(m,3H),2.41-2.09(m,4H),1.89-1.84(m,4H).LC/MS(ESI)m/z:C 32 H 34 FN 4 O 4 + [M+H] + Calculated 557.26; found 557.3.
Example 48: preparation of 3- (5- ((4- ((4- (4-chlorophenyl) -6, 6-dimethyl-5, 6-dihydro-2H-pyran-3-yl) methyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05672)
The title compound (GT-05672) (white solid, 15mg, yield 20.85%) was prepared according to the method of scheme 1. 1H NMR (400 MHz, DMSO-d 6) δ11.01 (s, 1H), 7.87-7.78 (m, 2H), 7.72 (dd, J= 16.4,8).2Hz,1H),7.44(d,J＝8.4Hz,2H),7.20(d,J＝8.3Hz,2H),5.14(dd,J＝13.2,5.1Hz,1H),4.42(dd,J＝51.5,17.8Hz,6H),3.42–3.12(m,10H),2.95–2.87(m,1H),2.61(d,J＝17.2Hz,1H),2.46–2.36(m,1H),2.20(s,2H),2.01(dd,J＝9.0,3.6Hz,1H),1.21(s,6H).LCMS(ESI)C 32 H 38 ClN 4 O 4 + [M+H] + Calculated 577.26, measured 577.3
Example 49: preparation of 3- (6- ((4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05363)
The title compound (GT-05363) was prepared according to the method of scheme 1 (white solid, 10mg, yield 10%). 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),7.96–7.81(m,1H),7.74–7.67(m,2H),7.41(d,J＝8.2Hz,2H),7.10(d,J＝7.6Hz,2H),5.12(dd,J＝13.2,5.0Hz,1H),4.51–4.34(m,4H),3.56–3.40(m,4H),3.08–3.05(m,2H),2.99–2.85(m,2H),2.86–2.71(m,2H),2.70–2.57(m,2H),2.47–2.36(m,1H),2.29–2.21(m,2H),2.09–1.93(m,3H),1.53–1.36(m,2H),0.96(s,6H).LCMS(ESI)C 33 H 40 ClN 4 O 3 + [M+H] + Calculated 575.28, measured 575.3.
Example 50: preparation of 3- (7- ((4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05360)
The title compound (GT-05360) was prepared according to the method of scheme 1 (white solid, 31mg, 30% yield). 1 H NMR(400MHz,DMSO-d6)δ11.04(s,1H),7.69(brs,3H),7.41(d,J＝8.0Hz,2H),7.11(d,J＝7.9Hz,2H),5.12(dd,J＝13.1,5.0Hz,1H),4.94–4.88(m,2H),4.49(d,J＝17.6Hz,1H),4.38(d,J＝17.9Hz,1H),3.67–3.61(m,4H),2.99–2.86(m,2H),2.73(s,1H),2.62(d,J＝17.2Hz,1H),2.56–2.51(m,4H),2.44–2.40(m,1H),2.32–2.24(m,2H),2.01(brs,3H),1.46–1.43(m,2H),0.95(s,6H).LCMS(ESI)C 33 H 40 ClN 4 O 3 + [M+H] + Calculated 575.28, measured 575.3.
Example 51: preparation of 3- (5- (2- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) ethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05361)
The title compound (GT-05361) was prepared according to the method of scheme 1 (white solid, 28mg, 26% yield). 1 H NMR(400MHz,DMSO-d6)δ10.98(s,1H),7.70(d,J＝8.0Hz,1H),7.50(s,1H),7.44–7.40(m,3H),7.12(d,J＝6.5Hz,2H),5.11(dd,J＝13.4,4.8Hz,1H),4.37(dd,J＝51.1,17.5Hz,2H),3.62–3.49(m,3H),3.14–3.05(m,3H),2.97–2.85(m,3H),2.69–2.54(m,4H),2.46–2.29(m,3H),2.26–2.19(m,2H),2.15–1.94(m,4H),1.54–1.38(m,2H),0.96(s,6H).LCMS(ESI)C 34 H 42 ClN 4 O 3 + [M+H] + Calculated 589.29, found 589.3.
Example 52: preparation of 3- (5- (3- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) propyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05362)
The title compound (GT-05362) was prepared according to the method of scheme 1 (white solid, 28mg, 33% yield). 1 H NMR(400MHz,DMSO-d6)δ10.98(s,1H),7.67(d,J＝7.8Hz,1H),7.47(s,1H),7.41–7.37(m,3H),7.12(d,J＝7.9Hz,2H),5.11(dd,J＝13.3,5.1Hz,1H),4.43(d,J＝17.3Hz,1H),4.30(d,J＝17.3Hz,1H),3.77–3.55(m,4H),3.39-3.31(m,4H),3.13–3.02(m,3H),2.99–2.85(m,2H),2.77–2.70(m,2H),2.60(d,J＝16.4Hz,1H),2.42–2.38(m,1H),2.35–2.23(m,2H),2.09–1.91(m,5H),1.45–1.41(m,2H),0.96(s,6H).LCMS(ESI)C 35 H 44 ClN 4 O 3 + [M+H] + Calculated 603.31, measured 603.3.
Example 53: preparation of 3- (4-fluoro-5- ((4- ((4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05390)
The title compound (GT-05390) was prepared according to the method of scheme 1 (white solid, 29mg, yield 32%). 1 H NMR(400MHz,DMSO-d6)δ11.02(s,1H),7.71–7.63(m,2H),7.21–7.11(m,4H),5.13(dd,J＝13.3,5.0Hz,1H),4.59–4.38(m,2H),4.16–3.90(m,2H),3.43–3.28(m,5H),3.15–3.03(m,2H),2.98–2.87(m,2H),2.81–2.72(m,1H),2.61(d,J＝17.6Hz,2H),2.45(dd,J＝13.2,4.9Hz,2H),2.28(brs,2H),2.02(brs,3H),1.45(t,J＝6.2Hz,2H),0.95(s,6H).LCMS(ESI)C 33 H 39 F 2 N 4 O 3 + [M+H] + Calculated 577.30, measured 577.3.
Example 54: preparation of 3- (6-fluoro-5- ((4- ((4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05391)
The title compound (GT-05391) was prepared according to the procedure for synthesis scheme 1 (white solid, 34mg, 38% yield). 1 H NMR(400MHz,DMSO-d6)δ11.02(s,1H),7.78–7.70(m,1H),7.59(d,J＝8.1Hz,1H),7.19(t,J＝8.8Hz,2H),7.13(t,J＝6.9Hz,2H),5.13(dd,J＝13.3,5.1Hz,1H),4.39(dd,J＝49.9,17.4Hz,2H),4.10-3.98(m,1H),3.30–3.20(m,5H),2.94–2.87(m,5H),2.72–2.63(m,3H),2.41(dd,J＝13.3,4.7Hz,1H),2.29(brs,2H),2.02(brs,3H),1.45(t,J＝6.2Hz,2H),0.95(s,6H).LCMS(ESI)C 33 H 39 F 2 N 4 O 3 + [M+H] + Calculated 577.30, measured 577.3.
Example 55: preparation of 3- (7-fluoro-5- ((4- ((4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05392)
The title compound (GT-05392) was prepared according to the method of scheme 1 (white solid, 7mg, yield 8%). 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),7.62–7.35(m,2H),7.24–7.09(m,4H),5.09(dd,J＝13.2,5.1Hz,1H),4.56–4.29(m,3H),3.37–3.27(m,4H),3.30–3.00(m,4H),2.98–2.85(m,2H),2.83–2.72(m,1H),2.60(d,J＝17.5Hz,2H),2.39(dd,J＝13.2,4.7Hz,1H),2.35–2.30(m,2H),2.11–1.91(m,3H),1.45(t,J＝6.1Hz,2H),0.95(s,6H).LCMS(ESI)C 33 H 39 F 2 N 4 O 3 + [M+H] + Calculated 577.30, measured 577.3.
Example 56: preparation of 3- (4- ((4- ((4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05393)
The title compound (GT-05393) was prepared according to the procedure of scheme 1 (white solid, 10mg, yield 11%). 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),7.74–7.70(m,2H),7.61–7.54(m,2H),7.20–7.10(m,4H),5.16(dd,J＝13.3,5.0Hz,2H),4.91(s,2H),4.69–4.26(m,5H),3.00–2.87(m,3H),2.71–2.56(m,4H),2.49–2.44(m,2H),2.25–2.21(m,2H),2.07–2.02(m,4H),1.46(t,J＝6.1Hz,2H),0.95(s,6H).LCMS(ESI)C 33 H 40 FN 4 O 3 + [M+H] + Calculated 559.31, measured 559.3.
Example 57: preparation of 3- (6- ((4- ((4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05394)
The title compound (GT-05394) was prepared according to the procedure for synthesis scheme 1 (white solid, 15mg, 16% yield). 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),7.90(brs,1H),7.83–7.54(m,3H),7.19–7.12(m,3H),5.12(dd,J＝13.2,4.9Hz,1H),4.53–4.30(m,4H),3.32–3.29(m,4H),3.26–3.10(m,4H),2.98–2.86(m,2H),2.61(d,J＝17.7Hz,2H),2.46–2.37(m,1H),2.33–2.27(m,2H),2.01(brs,3H),1.44(t,J＝6.4Hz,2H),0.95(s,6H).LCMS(ESI)C 33 H 40 FN 4 O 3 + [M+H] + Calculated 559.31, measured 559.3.
Example 58: preparation of 3- (5- ((4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -1, 4-diazepan-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05396)
The title compound (GT-05396) (white solid, 14mg, 17% yield) was prepared according to the method of FIG. 1. 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),7.89–7.86(m,1H),7.82–7.62(m,2H),7.46–7.42(m,2H),7.14(d,J＝7.6Hz,2H),5.14(dd,J＝10.9,2.6Hz,1H),4.67–4.24(m,4H),3.82–3.59(m,4H),3.10–2.89(m,4H),2.61(d,J＝17.2Hz,1H),2.49–2.42(m,1H),2.28–2.22(m,2H),2.07(s,4H),1.45(t,J＝6.0Hz,2H),0.95(s,6H).LCMS(ESI)C 34 H 42 ClN 4 O 3 + [M+H] + Calculated 589.29, found 589.3.
Example 59: preparation of 3- (5- ((6- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05529)
The title compound (GT-05529) was prepared according to the method of scheme 1 (white solid, 23mg, 26% yield). 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),7.59–7.55(m,2H),7.49–7.46(m,1H),7.39(d,J＝8.4Hz,1H),7.26–7.14(m,2H),5.17–5.05(m,1H),4.63–4.19(m,3H),4.05–4.00(m,1H),3.84–3.65(m,2H),3.31–3.13(m,4H),2.95–2.85(m,1H),2.77–2.62(m,3H),2.45–2.42(m,1H),2.33–2.15(m,2H),2.12–1.90(m,5H),1.44(t,J＝6.1Hz,2H),0.94(s,6H).LCMS(ESI)C 34 H 39 ClFN 4 O 3 + [M+H] + Calculated 605.27, measured 605.3.
Example 60: preparation of 3- (5- ((8- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -3, 8-diazabicyclo [3.2.1] octane-3-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05534)
The title compound (GT-05534) (white solid, 13mg, 45% yield) was prepared according to the method of scheme 1. 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),7.64–7.53(m,2H),7.44(d,J＝8.4Hz,2H),7.19(d,J＝8.4Hz,2H),5.12(dd,J＝13.3,5.1Hz,1H),4.55(d,J＝17.5Hz,1H),4.38(d,J＝17.5Hz,1H),3.75(d,J＝21.7Hz,4H),3.47–3.43(m,2H),3.00–2.79(m,3H),2.73–2.68(m,2H),2.61(d,J＝17.2Hz,1H),2.45–2.42(m,1H),2.29(s,2H),2.07–1.99(m,2H),2.04–1.94(m,1H),1.76(d,J＝8.3Hz,2H),1.46(t,J＝6.1Hz,2H),1.19(t,J＝7.3Hz,2H),0.96(s,6H).LCMS(ESI)C 35 H 41 ClFN 4 O 3 + [M+H] + Calculated 619.28, found 619.3.
Example 61: preparation of 3- (5- ((3- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptane-6-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05367)
The title compound (GT-05367) was prepared according to the method of scheme 1 (white solid, 11mg, 13% yield). 1 H NMR(400MHz,DMSO-d6)δ11.02(s,1H),7.68(d,J＝8.5Hz,1H),7.60(d,J＝8.8Hz,1H),7.39(d,J＝8.3Hz,2H),7.09(d,J＝8.2Hz,2H),5.17–5.12(m,2H),4.52–4.47(m,2H),4.38–4.32(m,3H),2.95–2.87(m,4H),2.63–2.57(m,2H),2.45–2.36(m,2H),2.35–2.14(m,4H),2.08–2.00(m,5H),1.44–1.41(m,2H),0.96(s,6H).LCMS(ESI)C 34 H 39 ClFN 4 O 3 + [M+H] + Calculated 605.27, measured 605.3.
Example 62: preparation of 3- (5- ((6- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05530)
The title compound (GT-05530) was prepared according to the method of scheme 1 (white solid, 25mg, yield 29%). 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),9.02(brs,1H),7.72(dd,J＝9.9,6.1Hz,1H),7.54–7.51(m,1H),7.50–7.47(m,1H),7.36(t,J＝7.9Hz,1H),7.28–7.12(m,2H),5.18–5.08(m,1H),4.44–4.42(m,1H),4.38–4.22(m,1H),4.12–3.92(m,1H),3.79–3.68(m,2H),3.52–3.40(m,3H),3.32–3.15(m,2H),3.08–2.83(m,2H),2.77–2.56(m,3H),2.46–2.35(m,1H),2.30–2.13(m,3H),2.11–2.02(m,4H),1.46–1.43(m,2H),0.95(s,6H).LCMS(ESI)C 34 H 39 ClFN 4 O 3 + [M+H] + Calculated 605.27, measured 605.3.
Example 63: preparation of 3- (5- ((8- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -3, 8-diazabicyclo [3.2.1] octane-3-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05535)
The title compound (GT-05535) was prepared according to the method of scheme 1 (white solid, 11mg, yield 38%). 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),7.75(s,1H),7.54(d,J＝8.7Hz,1H),7.44(d,J＝8.4Hz,2H),7.20(d,J＝8.4Hz,2H),5.12(dd,J＝13.3,5.1Hz,1H),4.44(d,J＝17.4Hz,1H),4.31(d,J＝17.4Hz,1H),3.83(brs,2H),3.75(brs,2H),3.49–3.41(m,3H),3.24–3.09(m,2H),2.99–2.86(m,1H),2.80(brs,1H),2.61(d,J＝16.9Hz,1H),2.47–2.31(m,3H),2.07(s,2H),2.05–1.96(m,1H),1.85(brs,2H),1.46(t,J＝6.2Hz,2H),1.21–1.15(m,2H),0.96(s,6H).LCMS(ESI)C 35 H 41 ClFN 4 O 3 + [M+H] + Calculated 619.28, found 619.3.
Example 64: preparation of 3- (5- ((3- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptane-6-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05383)
The title compound (GT-05383) was prepared according to the method of scheme 1 (white solid, 30mg, yield 30%). 1 H NMR(400MHz,DMSO-d6)δ11.02(s,1H),7.59–7.55(m,1H),7.53–7.49(m,1H),7.39(d,J＝8.4Hz,2H),7.09(d,J＝8.2Hz,2H),5.15–5.06(m,1H),4.64–4.25(m,6H),2.95–2.83(m,4H),2.67–2.57(m,2H),2.33-2.23(m,5H),2.02–1.91(m,5H),1.42(t,J＝6.7Hz,2H),0.96(d,J＝3.0Hz,6H).LCMS(ESI)C 34 H 39 ClFN 4 O 3 + [M+H] + Calculated 605.27, measured 605.3.
Example 65: preparation of 3- (5- ((6- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05531)
The title compound (GT-05531) was prepared according to the method of scheme 1 (white solid, 22mg, yield 25%). 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),7.53–7.47(m,1H),7.38–7.35(m,2H),7.26–7.21(m,2H),7.18–7.15(m,1H),5.08(dd,J＝13.3,5.0Hz,1H),4.53–4.50(m,1H),4.49–4.45(m,1H),4.41–4.29(m,1H),3.84–3.79(m,1H),3.63(s,1H),3.31–3.14(m,3H),3.12–3.01(m,1H),2.98–2.78(m,2H),2.62–2.51(m,3H),2.46–2.35(m,1H),2.30–2.19(m,2H),2.13–1.89(m,5H),1.45(d,J＝5.8Hz,2H),0.97(s,6H).LCMS(ESI)C 34 H 39 ClFN 4 O 3 + [M+H] + Calculated 605.27, measured 605.3.
Example 66: preparation of 3- (5- ((8- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -3, 8-diazabicyclo [3.2.1] octane-3-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05536)
The title compound (GT-05536) was prepared according to the method of scheme 1 (white solid, 12mg, 42% yield). 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),7.45(d,J＝8.4Hz,2H),7.39(s,1H),7.27–7.23(m,1H),7.21(t,d＝7.5Hz,2H),5.07(dd,J＝13.3,5.1Hz,1H),4.45(d,J＝17.8Hz,1H),4.32(d,J＝17.9Hz,1H),3.72(s,4H),3.49–3.47(m,2H),2.99–2.82(m,3H),2.73–2.62(m,2H),2.60(d,J＝16.7Hz,1H),2.40–2.33(m,3H),2.08(s,2H),2.01–1.98(m,1H),1.83(brs,2H),1.47(t,J＝6.2Hz,2H),1.19(t,J＝7.3Hz,2H),0.96(s,6H).LCMS(ESI)C 35 H 41 ClFN 4 O 3 + [M+H] + Calculated 619.29, found 619.3.
Example 67: preparation of 3- (5- ((4- (4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) piperazin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05525)
The title compound (GT-05525) (white solid, 6mg, yield 7%) was prepared according to the method of FIG. 1. 1 H NMR(400MHz,DMSO-d6)δ11.03(s,1H),7.75(s,1H),7.68(s,1H),7.43–7.36(m,2H),7.29–7.10(m,2H),5.14(dd,J＝13.2,4.7Hz,1H),4.60–4.41(m,4H),3.78-3.54(m,1H),3.29–3.18(m,3H),3.15–2.85(m,4H),2.61(d,J＝16.8Hz,1H),2.48–2.28(m,4H),2.22–2.11(m,1H),2.06–1.97(m,1H),1.92–1.88(m,1H),1.56–1.34(m,2H),0.98(s,6H).LCMS(ESI)C 33 H 37 ClFN 4 O 4 + [M+H] + Calculated 607.25, measured 607.3.
Example 68: preparation of 3- (5- ((4- (4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) piperazin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05526)
The title compound (GT-05526) was prepared according to the procedure of scheme 1 (white solid, 11mg, 13% yield))。 1 H NMR(400MHz,DMSO-d6)δ11.02(s,1H),7.87(s,1H),7.65(s,1H),7.38(d,J＝8.5Hz,2H),7.20(s,2H),5.14(dd,J＝13.2,5.0Hz,1H),4.49–4.32(m,4H),3.65(brs,1H),3.30–3.18(m,5H),3.09–3.05(m,1H),2.98–2.87(m,1H),2.61(d,J＝16.8Hz,1H),2.48–2.27(m,4H),2.22-2.16(m,1H),2.07–1.96(m,1H),1.92–1.87(m,1H),1.43(brs,2H),0.96(s,6H).LCMS(ESI)C 33 H 37 ClFN 4 O 4 + [M+H] + Calculated 607.25, measured 607.3.
Example 69: preparation of 3- (5- ((4- (4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) piperazin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05527)
The title compound (GT-05527) was prepared according to the method of scheme 1 (white solid, 5mg, yield 6%). 1 H NMR(400MHz,DMSO-d6)δ11.02(s,1H),7.56–7.49(m,2H),7.38(d,J＝8.5Hz,2H),7.29–7.10(m,2H),5.10(dd,J＝13.1,4.9Hz,1H),4.63–4.18(m,4H),3.77–3.49(m,2H),3.21–3.07(m,1H),3.03–2.81(m,3H),2.60(d,J＝16.3Hz,2H),2.47–2.26(m,4H),2.20–2.09(m,2H),2.05–1.96(m,1H),1.96–1.82(m,1H),1.50–1.44(m,2H),0.97(s,6H).LCMS(ESI)C 33 H 37 ClFN 4 O 4 + [M+H] + Calculated 607.25, measured 607.3.
Example 70: preparation of 3- (4- ((4- (4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05528)
The title compound (GT-05528) was prepared according to the method of scheme 1 (white solid, 9mg, yield 11%). 1 H NMR(400MHz,DMSO-d6)δ11.06(s,1H),7.97–7.69(m,2H),7.65–7.59(m,1H),7.43–7.38(m,2H),7.29–7.15(m,2H),5.26–5.09(m,1H),4.74–4.62(m,1H),4.54–4.20(m,3H),3.74–3.63(m,1H),3.33–3.18(m,4H),3.07–3.88(m,3H),2.64(d,J＝17.8Hz,1H),2.41–2.27(m,4H),2.27–2.11(m,1H),2.09–2.01(m,2H),1.92–1.88(m,1H),1.60–1.36(m,2H),0.97(s,6H).LCMS(ESI)C 33 H 38 ClN 4 O 4 + [M+H] + Calculated value 589.26, actualMeasured 589.3.
Example 71: preparation of 3- (5- (4- ((4- (4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) piperazin-1-yl) methyl) phenyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05359)
The title compound (GT-05359) was prepared according to the method of FIG. 6 (white solid, 11mg, 16% yield). 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),7.93(s,1H),7.87–7.83(m,1H),7.57–7.50(m,2H),7.44–7.38(m,2H),7.23–7.15(m,4H),6.81(d,J＝7.9Hz,1H),5.15(dd,J＝13.2,5.1Hz,1H),4.53(d,J＝17.5Hz,1H),4.40(d,J＝17.5Hz,1H),4.36–4.22(m,1H),4.13–4.08(m,1H),3.14–3.02(m,4H),2.95–2.89(m,2H),2.67–2.58(m,1H),2.43–2.30(m,4H),2.22–2.08(m,2H),2.07–2.00(m,1H),1.95–1.87(m,1H),1.51–1.40(m,3H),0.97(s,6H).LCMS(ESI)C 39 H 42 ClN 4 O 4 + [M+H] + Calculated 665.29, measured 665.3.
Example 72: preparation of 3- (5- ((3- (4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) -3, 6-diazabicyclo [3.1.1] heptan-6-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05521)
The title compound (GT-05521) was prepared according to the method of scheme 1 (white solid, 10mg, 12% yield). 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),7.86–7.73(m,1H),7.72–7.61(m,1H),7.50–7.33(m,3H),7.28–7.16(m,2H),5.13(dd,J＝13.3,5.1Hz,1H),4.62–4.58(m,1H),4.51–4.43(m,1H),4.37–4.19(m,2H),4.17–4.10(m,1H),3.80–3.63(m,1H),3.50–3.39(m,1H),3.25–3.13(m,2H),2.95–2.89(m,1H),2.61(d,J＝17.6Hz,2H),2.49–2.33(m,3H),2.26–2.17(m,1H),2.12–1.96(m,2H),1.93–1.89(m,1H),1.59–1.33(m,2H),0.99(d,J＝6.6Hz,6H).LCMS(ESI)C 34 H 38 ClN 4 O 4 + [M+H] + Calculated 601.26, found 601.3.
Example 73: preparation of 3- (5- ((3- (4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) -3, 8-diazabicyclo [3.2.1] octane-8-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05522)
The title compound (GT-05522) was prepared according to the method of scheme 1 (white solid, 12mg, 15% yield). 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),7.97–7.64(m,3H),7.45–7.36(m,3H),7.15(d,J＝7.7Hz,1H),5.14(dd,J＝12.7,4.7Hz,1H),4.51–4.46(m,2H),4.26–4.16(m,2H),4.16–4.04(m,1H),3.93–3.80(m,1H),3.76(brs,1H),3.69–3.52(m,1H),3.27–3.18(m,2H),3.00–2.85(m,1H),2.75–2.68(m,1H),2.61(d,J＝17.4Hz,1H),2.47–2.21(m,4H),2.16–2.10(m,1H),2.02–1.99(m,2H),1.90-1.88(m,1H),1.65–1.63(m,1H),1.52–1.43(m,2H),0.95(s,6H).LCMS(ESI)C 35 H 40 ClN 4 O 4 + [M+H] + Calculated 615.27, measured 615.3.
Example 74: preparation of 3- (5- ((8- (4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) -3, 8-diazabicyclo [3.2.1] octane-3-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05523)
The title compound (GT-05523) was prepared according to the method of scheme 1 (white solid, 12mg, 15% yield). 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),7.90–7.86(m,1H),7.79–7.69(m,2H),7.41(d,J＝7.7Hz,2H),7.26(d,J＝7.7Hz,2H),5.20–5.04(m,1H),4.62–4.13(m,4H),3.91(brs,1H),3.41-3.28(m,4H),3.21–3.07(m,2H),3.03–2.82(m,2H),2.63(t,J＝17.3Hz,2H),2.47–2.21(m,4H),2.07–1.94(m,2H),1.91–1.76(m,2H),1.56–1.37(m,2H),0.97(s,6H).LCMS(ESI)C 35 H 40 ClN 4 O 4 + [M+H] + Calculated 615.27, measured 615.3.
Example 75: preparation of 3- (5- ((5- (4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05524)
The title compound (GT-05524) was prepared according to the method of scheme 1 (white solid, 10mg, 12% yield). 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),7.85–7.75(m,2H),7.74–7.65(m,1H),7.51–7.33(m,2H),7.32–7.18(m,2H),5.14(dd,J＝13.1,5.1Hz,1H),4.66–4.09(m,6H),3.73–3.60(m,1H),3.27–3.22(m,2H),3.15–3.13(m,1H),3.05–2.84(m,2H),2.61(d,J＝16.1Hz,1H),2.43(dd,J＝13.1,3.8Hz,1H),2.39–2.10(m,4H),2.03–1.99(m,2H),1.53–1.34(m,2H),0.97(s,6H).LCMS(ESI)C 34 H 38 ClN 4 O 4 + [M+H] + Calculated 601.26, found 601.3.
Example 76: preparation of 3- (5- (5- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -2, 5-diazabicyclo [2.2.1] heptane-2-carbonyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05541)
Referring to the procedure of FIG. 6, starting materials 2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindoline-5-carboxylic acid and 2- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl) were reacted]-2-yl) methyl) -2, 5-diazabicyclo [2.2.1]The target compound (GT-05541) (white solid, 51mg, yield 60%) was prepared by amide condensation of heptane. 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),7.80–7.74(m,1H),7.64(d,J＝29.1Hz,1H),7.57-7.52(m,1H),7.42–7.35(m,1H),7.34–7.15(m,3H),5.14(dt,J＝11.3,5.6Hz,1H),4.71–4.67(m,1H),4.55–4.36(m,2H),4.17(t,J＝28.0Hz,1H),3.47–3.41(m,1H),3.27–3.00(m,2H),3.00–2.85(m,2H),2.61(d,J＝16.9Hz,1H),2.46–2.35(m,1H),2.30–2.23(m,3H),2.07–2.00(m,2H),1.83–1.75(m,1H),1.63–1.60(m,1H),1.47–1.42(m,2H),0.97(s,6H).LCMS(ESI)C 34 H 36 ClN 4 O 5 + [M+H] + Calculated 615.24, measured 615.3.
Example 77: preparation of 3- (5- (2- (4- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) ethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05876)
The title compound (GT-05876) was prepared according to the method of scheme 1 (white solid, 37mg, 50% yield). 1 H NMR(400MHz,DMSO-d6)δ10.99(s,1H),7.69(d,J＝7.8Hz,1H),7.58–7.51(m,3H),7.49–7.47(m,2H),7.45–7.38(m,3H),7.35–7.26(m,1H),5.11(dd,J＝13.3,5.1Hz,1H),4.48–4.37(m,2H),4.09–3.82(m,2H),3.37–3.25(m,7H),3.24–3.04(m,4H),3.00–2.84(m,2H),2.60(d,J＝16.2Hz,1H),2.48–2.32(m,1H),2.11–1.91(m,1H).LCMS(ESI)C 32 H 34 ClN 4 O 3 + [M+H] + Calculated 557.23, measured 557.3.
Example 78: preparation of 3- (5- (3- (4- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) propyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05893)
The title compound (GT-05893) was prepared according to the method of scheme 1 (white solid, 38mg, yield 48%). 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),7.79(brs,1H),7.66(d,J＝7.8Hz,1H),7.52(d,J＝8.4Hz,2H),7.49–7.35(m,6H),7.34–7.26(m,1H),5.10(dd,J＝13.3,5.0Hz,1H),4.45–4.27(m,3H),3.45–3.30(m,4H),3.18–3.06(m,4H),2.98–2.85(m,2H),2.77–2.73(m,3H),2.60(d,J＝17.0Hz,2H),2.46–2.32(m,1H),2.05–1.97(m,3H).LCMS(ESI)C 33 H 36 ClN 4 O 3 + [M+H] + Calculated 571.25, found 571.3.
Example 79: preparation of 3- (4- ((4- ((4 '-fluoro-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05861)
The title compound (GT-05861) (white solid, 41mg, yield 45%) was prepared according to the method of FIG. 1. 1 H NMR(400MHz,DMSO-d6)δ11.03(s,1H),7.75(brs,2H),7.57(brs,1H),7.29–7.03(m,4H),5.15(dd,J＝13.2,4.9Hz,1H),4.71(brs,1H),4.44–4.40(m,1H),3.39–3.33(m,4H),3.30–3.10(m,4H),3.03–2.85(m,3H),2.73(brs,1H),2.63(d,J＝17.0Hz,2H),2.43–2.15(m,5H),2.08–1.94(m,1H),1.68(s,4H).LCMS(ESI)C 31 H 36 FN 4 O 3 + [M+H] + Calculated 531.28, measured 531.3.
Example 80: preparation of 3- (5- ((1- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) azetidin-3-yl) amino) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05382)
The title compound (GT-05382) was prepared according to the method of FIG. 2 (white solid, 12mg, 19% yield). 1 H NMR(400MHz,DMSO-d6)δ10.93(s,1H),7.73–7.62(m,1H),7.58–7.56(m,1H),7.53–7.47(m,3H),7.46–7.43(m,2H),7.41–4.37(m,1H),7.37–7.27(m,1H),6.60(brs,1H),6.58(brs,1H),5.02(dd,J＝13.3,5.1Hz,1H),4.56–4.38(m,3H),4.28(d,J＝17.0Hz,2H),4.16(d,J＝16.9Hz,2H),4.05–3.96(m,1H),3.78–3.71(m,1H),2.98–2.93(m,1H),2.60–2.51(m,1H),2.39–2.33(m,1H),1.98–1.90(m,1H).LCMS(ESI)C 29 H 28 ClN 4 O 3 + [M+H] + Calculated 515.18, found 515.2.
Example 81: preparation of 3- (4- ((4- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) amino) piperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-04947)
The title compound (GT-04947) was prepared according to the method of scheme 1 (white solid, 39mg, yield 49%). 1 H NMR(400MHz,DMSO)δ11.07(s,1H),7.88(d,J＝8.4Hz,1H),7.84(d,J＝7.7Hz,1H),7.65(t,J＝7.5Hz,1H),7.53–7.45(m,3H),7.40(d,J＝8.5Hz,1H),7.22–7.17(m,1H),7.01–6.93(m,1H),6.81(d,J＝8.0Hz,1H),6.73(t,J＝7.4Hz,1H),5.19(dd,J＝12.8,4.7Hz,1H),4.73–4.68(m,1H),4.56–4.44(m,2H),4.35(d,J＝4.5Hz,2H),3.23–3.04(m,2H),3.04–2.88(m,2H),2.65(d,J＝15.8Hz,1H),2.36–2.32(m,1H),2.17–1.94(m,4H),1.67–1.59(m,1H).LCMS(ESI)C 31 H 32 ClN 4 O 3 + [M+H] + Calculated 543.22, measured 543.3.
Example 82: preparation of 3- (5- ((8- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05618)
The title compound (GT-05618) (white solid, 54mg, yield 62%) was prepared according to the method of FIG. 1. 1 H NMR(400MHz,DMSO-d6)δ10.99(s,1H),8.04(brs,1H),7.71–7.68(m,1H),7.64–7.49(m,4H),7.46–7.41(m,3H),7.37–7.31(m,1H),5.10(dd,J＝13.3,5.2Hz,1H),4.36(dd,J＝51.8,17.7Hz,2H),4.19(brs,1H),3.84–3.54(m,4H),3.54–3.47(m,4H),2.96–2.89(m,2H),2.80–2.54(m,3H),2.46–2.28(m,1H),2.08–1.94(m,1H),1.94–1.76(m,1H),1.35–1.26(m,1H).LCMS(ESI)C 33 H 34 ClN 4 O 3 + [M+H] + Calculated 569.23, measured 569.3.
Example 83: preparation of 3- (5- ((5- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) -2, 5-diazabicyclo [2.2.2] oct-2-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05619)
The title compound (GT-05619) (white solid, 40mg, yield 46%) was prepared according to the method of scheme 1. 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),8.17(brs,1H),7.90(brs,1H),7.80(d,J＝4.8Hz,2H),7.64–7.36(m,6H),7.29(brs,1H),5.14(dd,J＝12.9,5.0Hz,1H),4.70–4.22(m,5H),4.01–3.55(m,3H),3.78–3.56(m,2H),3.32–3.14(m,3H),3.00–2.87(m,1H),2.68–2.57(m,1H),2.49–2.46(m,1H),2.33–2.09(m,1H),2.07–1.95(m,1H),1.90–1.43(m,2H).LCMS(ESI)C 33 H 34 ClN 4 O 3 + [M+H] + Calculated 569.23, measured 569.2.
Example 84: preparation of 3- (5- ((4- (2- (5-chloropyridin-2-yl) benzyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05860)
The title compound (GT-05860) was prepared according to the procedure of scheme 1 (white solid, 32mg, 59% yield). 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),8.90(s,1H),8.15(d,J＝7.5Hz,1H),7.96–7.67(m,6H),7.65–7.53(m,2H),5.14(dd,J＝13.2,5.1Hz,1H),4.69–4.06(m,7H),3.30–3.01(m,5H),2.98–2.83(m,2H),2.61(d,J＝16.7Hz,2H),2.43(dd,J＝13.0,4.6Hz,1H),2.03–1.99(m,1H).LCMS(ESI)C 30 H 31 ClN 5 O 3 + [M+H] + Calculated 544.21, measured 544.3.
Example 85: preparation of 3- (5- ((4- ((4 '-chloro- [1,1' -biphenyl ] -3-yl) methyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05629)
The title compound (GT-05629) (white solid, 33mg, yield 37%) was prepared according to the method of FIG. 1. 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),7.93(s,1H),7.81–7.67(m,5H),7.59–7.49(m,5H),5.12(dd,J＝13.4,5.0Hz,1H),4.48–4.31(m,4H),3.90–3.62(m,2H),3.57–3.41(m,4H),3.16–3.09(m,2H),3.00–2.81(m,2H),2.67–2.51(m,2H),2.45–2.33(m,1H),2.09–1.88(m,1H).LCMS(ESI)C 31 H 32 ClN 4 O 3 + [M+H] + Calculated 543.22, measured 543.3.
Example 86: preparation of 3- (5- ((4- (3- (5-chloropyridin-2-yl) benzyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05596)
The title compound (GT-05596) was prepared according to the method of scheme 1 (white solid, 9mg, yield 10%). 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),8.73(t,J＝1.6Hz,1H),8.33(s,1H),8.15(d,J＝7.2Hz,1H),8.08(d,J＝1.5Hz,2H),7.79(d,J＝7.9Hz,2H),7.74–7.64(m,2H),7.61–7.57(m,1H),5.21–5.11(m,1H),4.69–4.17(m,8H),3.38–3.19(m,5H),2.95–2.89(m,2H),2.60(d,J＝17.1Hz,1H),2.46–2.38(m,1H),2.05–1.95(m,1H).LCMS(ESI)C 30 H 31 ClN 5 O 3 + [M+H] + Calculated 544.21, measured 544.2.
Example 87: preparation of 3- (1-oxo-5- ((4- (3- (thiophen-2-yl) benzyl) piperazin-1-yl) methyl) isoindolin-2-yl) piperidine-2, 6-dione (GT-05597)
The title compound (GT-05597) was prepared according to the method of scheme 1 (white solid, 52mg, 56% yield). 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),7.97–7.90(m,1H),7.85–7.75(m,2H),7.74–7.64(m,2H),7.59(d,J＝5.1Hz,1H),7.56(d,J＝3.5Hz,1H),7.48(d,J＝4.0Hz,2H),7.17(dd,J＝5.0,3.7Hz,1H),5.13(dd,J＝13.3,5.1Hz,1H),4.50–4.33(m,5H),3.62–3.54(m,4H),3.34–3.24(m,4H),3.12–3.05(m,1H),2.99–2.86(m,1H),2.63–2.58(m,1H),2.46–2.37(m,1H),2.03–1.98(m,1H).LCMS(ESI)C 29 H 31 N 4 O 3 S + [M+H] + Calculated 515.21, found 515.2.
Example 88: preparation of 3- (5- ((4- (3- (furan-2-yl) benzyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05692)
The title compound (GT-05692) was prepared according to the method of scheme 1 (white solid, 34mg, 36% yield). 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),7.93(t,J＝11.8Hz,1H),7.83–7.71(m,4H),7.71–7.58(m,1H),7.51–7.44(m,2H),6.98(d,J＝3.3Hz,1H),6.63(dd,J＝3.3,1.7Hz,1H),5.13(dd,J＝13.3,4.7Hz,1H),4.59–4.16(m,7H),3.31–3.20(m,4H),2.95–2.89(m,2H),2.67–2.57(m,3H),2.41(dd,J＝12.5,4.2Hz,1H),2.04–1.99(m,1H).LCMS(ESI)C 29 H 31 N 4 O 4 + [M+H] + Calculated 499.23, found 499.2.
Example 89: preparation of 3- (5- ((4- (3- (1H-pyrrol-2-yl) benzyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05733)
The title compound (GT-05733) (white solid, 31mg, yield 32%) was prepared according to the method of FIG. 1. 1 H NMR(400MHz,DMSO-d6)δ11.34(s,1H),11.00(s,1H),7.92–7.76(m,3H),7.66(d,J＝7.2Hz,2H),7.41(t,J＝7.7Hz,1H),7.32–7.29(m,1H),6.88(d,J＝1.3Hz,1H),6.54(s,1H),6.13(dd,J＝5.6,2.5Hz,1H),5.13(dd,J＝13.3,5.0Hz,1H),4.61–4.16(m,7H),3.22–3.06(m,5H),3.00–2.86(m,3H),2.60(d,J＝17.4Hz,3H),2.41(dd,J＝13.2,4.7Hz,1H),2.05–1.93(m,1H).LCMS(ESI)C 29 H 32 N 5 O 3 + [M+H] + Calculated 498.25, found 498.3.
Example 90: preparation of 3- (5- ((4- ((4 '-chloro- [1,1' -biphenyl ] -4-yl) methyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05598)
The title compound (GT-05598) was prepared according to the method of scheme 1 (white solid, 45mg, 50% yield). 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),7.80–7.70(m,9H),7.58–7.48(m,2H),5.13(dd,J＝13.3,5.0Hz,1H),4.50–4.33(m,5H),3.76-3.59(m,4H),3.37–3.13(m,5H),2.99–2.85(m,1H),2.61(d,J＝16.7Hz,1H),2.42(dd,J＝13.2,4.5Hz,1H),2.07–1.91(m,1H).LCMS(ESI)C 31 H 32 ClN 4 O 3 + [M+H] + Calculated 543.22, measured 543.2.
Example 91: preparation of 3- (5- ((4- (4- (5-chloropyridin-2-yl) benzyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05872)
Preparation of the target Compound (GT-05872) (white) by the method according to Synthesis scheme 1Solid, 39mg, yield 44%). 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),8.73(dd,J＝2.3,0.8Hz,1H),8.15(d,J＝8.2Hz,2H),8.10–8.01(m,2H),7.79(d,J＝7.8Hz,2H),7.70(d,J＝5.7Hz,3H),5.13(dd,J＝13.3,5.1Hz,1H),4.58–4.20(m,6H),3.41–3.32(m,4H),3.33–3.08(m,4H),2.98–2.86(m,1H),2.61(d,J＝16.7Hz,1H),2.42(dd,J＝13.1,4.4Hz,1H),2.06–1.95(m,1H).LCMS(ESI)C 30 H 31 ClN 5 O 3 + [M+H] + Calculated 544.21, measured 544.2.
Example 92: preparation of 3- (1-oxo-5- ((4- (4- (thiophen-2-yl) benzyl) piperazin-1-yl) methyl) isoindolin-2-yl) piperidine-2, 6-dione (GT-05640)
The title compound (GT-05640) (white solid, 9mg, yield 10%) was prepared according to the method of FIG. 1. 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),7.81–7.66(m,4H),7.65–7.43(m,5H),7.16(dd,J＝5.0,3.7Hz,1H),5.13(dd,J＝13.4,4.8Hz,1H),4.49–4.43(m,5H),3.42–3.35(m,4H),3.24–3.04(m,4H),2.94–2.88(m,1H),2.69–2.57(m,2H),2.41(dd,J＝15.2,2.4Hz,1H),2.08–1.94(m,1H).LCMS(ESI)C 29 H 31 N 4 O 3 S + [M+H] + Calculated 515.21, found 515.2.
Example 93: preparation of 3- (5- ((4- (4- (furan-2-yl) benzyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05693)
The title compound (GT-05693) was prepared according to the method of scheme 1 (white solid, 58mg, 61% yield). 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),7.79–7.75(m,5H),7.72–7.66(m,1H),7.63–7.61(m,2H),7.04(d,J＝3.3Hz,1H),6.62(dd,J＝3.4,1.8Hz,1H),5.13(dd,J＝13.3,5.0Hz,1H),4.60–4.07(m,7H),3.29–3.14(m,4H),3.07–2.95(m,1H),2.99–2.84(m,2H),2.68–2.56(m,2H),2.44–2.40(m,1H),2.04–1.99(m,1H).LCMS(ESI)C 29 H 31 N 4 O 4 + [M+H] + Calculated 499.23, found 499.3.
Example 94: preparation of 3- (5- ((4- (4- (1H-pyrrol-2-yl) benzyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05734)
The title compound (GT-05734) was prepared according to the method of scheme 1 (white solid, 32mg, 33% yield). 1 H NMR(400MHz,DMSO-d6)δ11.39(s,1H),11.00(s,1H),7.83–7.73(m,2H),7.69–7.64(m,3H),7.53–7.51(m,2H),6.88(s,1H),6.59(s,1H),6.13(dd,J＝5.6,2.5Hz,1H),5.13(dd,J＝13.3,5.1Hz,1H),4.64–4.04(m,7H),3.25–3.06(m,5H),2.99–2.86(m,2H),2.60(d,J＝16.8Hz,2H),2.45–2.34(m,1H),2.06–1.90(m,1H).LCMS(ESI)C 29 H 32 N 5 O 3 + [M+H] + Calculated 498.25, found 498.2.
Example 95: preparation of 3- (5- ((4- ((6- (4-chlorophenyl) pyridin-3-yl) methyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05632)
The title compound (GT-05632) (white solid, 49mg, yield 55%) was prepared according to the method of FIG. 1. 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),8.81(s,1H),8.15(d,J＝8.6Hz,2H),8.10(d,J＝7.7Hz,2H),7.80(d,J＝7.8Hz,2H),7.72–7.69(m,1H),7.58(d,J＝8.7Hz,2H),5.13(dd,J＝13.2,5.0Hz,1H),4.51–4.34(m,6H),3.49–3.42(m,4H),3.39–3.32(m,4H),2.99–2.84(m,2H),2.66–2.54(m,1H),2.44–2.40(m,1H),2.07–1.89(m,1H).LCMS(ESI)C 30 H 31 ClN 5 O 3 + [M+H] + Calculated 544.21, measured 544.2.
Example 96: preparation of 3- (5- ((4- ([ 2,4' -bipyridyl ] -5-ylmethyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05633)
The title compound (GT-05633) was prepared according to the method of scheme 1 (white solid, 32mg, 34% yield). 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),9.09(s,1H),9.04(d,J＝6.6Hz,2H),8.71(d,J＝6.7Hz,2H),8.51(d,J＝8.2Hz,1H),8.42(d,J＝8.3Hz,1H),7.94(s,1H),7.81(q,J＝8.1Hz,2H),5.14(dd,J＝13.2,5.1Hz,1H),4.71–4.33(m,10H),3.94–3.83(m,4H),2.99–2.87(m,1H),2.61(d,J＝16.9Hz,1H),2.43(dd,J＝13.2,4.6Hz,1H),2.03–2.00(m,1H).LCMS(ESI)C 29 H 31 N 6 O 3 + [M+H] + Calculated value 511.25, found 511.2.
Example 97: preparation of 3- (1-oxo-5- ((4- ((5-phenylpyrazin-2-yl) methyl) piperazin-1-yl) methyl) isoindolin-2-yl) piperidine-2, 6-dione (GT-05544)
The title compound (GT-05544) was prepared according to the method of scheme 1 (white solid, 32mg, 34% yield). 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),9.30(s,1H),8.90(s,1H),8.18(dd,J＝7.9,1.6Hz,2H),7.90–7.70(m,3H),7.64–7.51(m,3H),5.14(dd,J＝13.3,5.1Hz,1H),4.60–4.29(m,6H),3.45–3.41(m,4H),3.33–3.23(m,4H),2.99–2.85(m,1H),2.61(d,J＝16.6Hz,1H),2.45–2.40(m,1H),2.06–1.93(m,1H).LCMS(ESI)C 29 H 31 N 6 O 3 + [M+H] + Calculated 511.25, found 511.2.
Example 98: preparation of 3- (5- ((4- ((5- (4-chlorophenyl) thiophen-2-yl) methyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05625)
The title compound (GT-05625) (white solid, 24mg, yield 27%) was prepared according to the method of FIG. 1. 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),7.80(d,J＝7.7Hz,2H),7.70–7.62(m,3H),7.49(d,J＝8.6Hz,3H),7.24(brs,1H),5.13(dd,J＝13.2,5.2Hz,1H),4.60–4.17(m,6H),3.35–3.26(m,4H),3.17–3.00(m,4H),2.91–2.88(m,2H),2.61(d,J＝16.7Hz,1H),2.44–2.39(m,1H),2.04–1.95(m,1H).LCMS(ESI)C 29 H 30 ClN 4 O 3 S + [M+H] + Calculated 549.17, measured 549.2.
Example 99: preparation of 3- (5- ((4- ([ 2,2' -bisthien ] -5-ylmethyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05624)
The title compound (GT-05624) was prepared according to the method of scheme 1 (white solid, 29mg, 31% yield). 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),7.80(d,J＝7.7Hz,2H),7.70(d,J＝6.9Hz,1H),7.54(d,J＝4.5Hz,1H),7.31(d,J＝3.0Hz,1H),7.25(brs,1H),7.21(brs,1H),7.10(dd,J＝5.1,3.6Hz,1H),5.13(dd,J＝13.2,5.1Hz,1H),4.51–4.34(m,6H),3.40–3.32(m,4H),3.24–2.96(m,4H),2.96–2.86(m,1H),2.61(d,J＝16.4Hz,1H),2.42(dd,J＝13.0,4.4Hz,1H),2.05–1.94(m,1H).LCMS(ESI)C 27 H 29 N 4 O 3 S 2 + [M+H] + Calculated 521.17, found 521.2.
Example 100: preparation of 3- (5- ((4- ((5- (4-chlorophenyl) furan-2-yl) methyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05694)
The title compound (GT-05694) was prepared according to the method of scheme 1 (white solid, 34mg, 37% yield). 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),7.84–7.66(m,5H),7.51(d,J＝8.6Hz,2H),7.05(d,J＝3.2Hz,1H),6.75(s,1H),5.13(dd,J＝13.1,5.1Hz,1H),4.64–4.21(m,7H),3.27–3.14(m,5H),2.99–2.83(m,2H),2.63(t,J＝18.5Hz,2H),2.42(dd,J＝13.2,4.5Hz,1H),2.02–1.91(m,1H).LCMS(ESI)C 29 H 30 ClN 4 O 4 + [M+H] + Calculated 533.20, found 533.3.
Example 101: preparation of 3- (1-oxo-5- ((4- ((5- (thiophen-2-yl) furan-2-yl) methyl) piperazin-1-yl) methyl) isoindolin-2-yl) piperidine-2, 6-dione (GT-05627)
The title compound (GT-05627) was prepared according to the method of scheme 1 (white solid, 27mg, yield 28%). 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),7.87–7.76(m,2H),7.71(d,J＝7.1Hz,1H),7.57(d,J＝5.0Hz,1H),7.42(d,J＝3.2Hz,1H),7.13(dd,J＝4.9,3.7Hz,1H),6.79(d,J＝3.2Hz,1H),6.74(s,1H),5.13(dd,J＝13.3,5.1Hz,1H),4.61–4.17(m,6H),3.39–3.28(m,4H),3.24–3.02(m,4H),2.97–2.87(m,1H),2.60(d,J＝16.9Hz,1H),2.46–2.32(m,1H),2.07–1.95(m,1H).LCMS(ESI)C 27 H 29 N 4 O 4 S + [M+H] + Calculated 505.19, found 505.2.
Example 102: preparation of 3- (5- ((4- ([ 2,2' -bisfuran ] -5-ylmethyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05695)
The title compound (GT-05695) was prepared according to the method of scheme 1 (white solid, 37mg, yield 38%). 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),7.85–7.66(m,4H),6.73(brs,3H),6.64–6.59(m,1H),5.13(dd,J＝13.2,5.1Hz,1H),4.61–4.17(m,7H),3.29–3.01(m,5H),2.99–2.86(m,2H),2.63(t,J＝16.7Hz,2H),2.42(dd,J＝13.1,4.5Hz,1H),2.09–1.88(m,1H).LCMS(ESI)C 27 H 29 N 4 O 5 + [M+H] + Calculated 489.21, measured 489.2.
Example 103: preparation of 3- (5- ((1- (4 '-chloro- [1,1' -biphenyl ] -2-carbonyl) azetidin-3-yl) amino) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-04397)
The title compound (GT-04397) was prepared according to the method of FIG. 6 (white solid, 24mg, 36% yield). 1 H NMR(400MHz,MeOD)δ7.49–7.33(m,9H),6.51–6.44(m,1H),6.39(s,1H),4.97(dd,J＝13.3,5.2Hz,1H),4.30–4.19(m,3H),4.06–4.01(m,1H),3.94–3.85(m,1H),3.69(dd,J＝10.8,4.7Hz,1H),3.33–3.26(m,1H),2.86–2.73(m,1H),2.69–2.63(m,1H),2.31–2.21(m,1H),2.07–1.97(m,1H).LCMS(ESI)C 29 H 26 ClN 4 O 4 + [M+H] + Calculated 529.16, measured 529.2.
Example 104: preparation of 3- (5- (4- ((4- (4 '-chloro- [1,1' -biphenyl ] -2-carbonyl) piperazin-1-yl) methyl) phenyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05874)
The title compound (GT-05874) (white solid, 16mg, yield 27%) was prepared according to the method of FIG. 6. 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),7.93(s,1H),7.83(brs,4H),7.72–7.36(m,10H),5.15(dd,J＝13.2,5.1Hz,1H),4.55–4.38(m,4H),4.32(brs,1H),3.30–3.23(m,4H),3.07(brs,2H),3.02–2.86(m,2H),2.62(d,J＝16.4Hz,2H),2.44(dd,J＝13.3,4.4Hz,1H),2.04–1.97(m,1H).LCMS(ESI)C 37 H 34 ClN 4 O 4 + [M+H] + Calculated 633.23, measured 633.3.
Example 105: preparation of 3- (5- ((7- (4 '-chloro- [1,1' -biphenyl ] -2-carbonyl) -2, 7-diazaspiro [3.5] nonan-2-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05620)
The title compound (GT-05620) (white solid, 52mg, yield 62) was prepared according to the method of FIG. 1％)。 1 H NMR(400MHz,DMSO-d6)δ11.43–11.20(m,1H),11.00(s,1H),7.78(d,J＝7.7Hz,2H),7.67(d,J＝7.4Hz,1H),7.53–7.39(m,7H),7.36–7.26(m,1H),5.13(dd,J＝13.3,5.3Hz,1H),4.50–4.32(m,4H),3.88–3.74(m,4H),3.66–3.54(m,2H),3.06–2.86(m,2H),2.85–2.70(m,1H),2.61(d,J＝17.4Hz,1H),2.46–2.34(m,1H),2.08–1.93(m,1H),1.94–1.71(m,1H),1.70–1.43(m,2H),1.06–0.94(m,1H).LCMS(ESI)C 34 H 34 ClN 4 O 4 + [M+H] + Calculated 597.23, measured 597.3.
Example 106: preparation of 3- (5- (3- (4 '-chloro- [1,1' -biphenyl ] -2-carbonyl) -3, 8-diazabicyclo [3.2.1] oct-8-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05875)
The title compound (GT-05875) was prepared according to the method of FIG. 6 (white solid, 34mg, 52% yield). 1 H NMR(400MHz,DMSO-d6)δ10.93(s,1H),7.58(s,2H),7.54–7.41(m,4H),7.36–7.33(m,1H),7.28(d,J＝8.4Hz,1H),7.24(dd,J＝7.6,2.3Hz,1H),6.98–6.89(m,1H),6.87–6.81(m,1H),5.10–4.94(m,1H),4.45–4.41(m,1H),4.35–4.23(m,1H),4.23–4.08(m,2H),3.92(d,J＝13.2Hz,1H),3.12(dd,J＝50.6,12.2Hz,2H),2.99–2.84(m,1H),2.71–2.54(m,3H),2.40–2.34(m,1H),2.05–1.83(m,2H),1.83–1.68(m,1H),1.65–1.42(m,1H),1.17–1.12(m,1H).LCMS(ESI)C 32 H 30 ClN 4 O 4 + [M+H] + Calculated 569.20, measured 569.2.
Example 107: preparation of 3- (5- ((8- (4 '-chloro- [1,1' -biphenyl ] -2-carbonyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05542)
The title compound (GT-05542) was prepared according to the method of scheme 1 (white solid, 60mg, yield 70%). 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),7.95–7.91(m,1H),7.82–7.69(m,2H),7.59–7.48(m,6H),7.41–7.36(m,2H),5.12(dd,J＝12.9,3.5Hz,1H),4.69–4.59(m,1H),4.55–4.21(m,3H),3.67–3.61(m,1H),3.56–3.41(m,4H),3.24–3.09(m,1H),3.13–2.99(m,1H),2.96–2.92(m,2H),2.68–2.56(m,1H),2.44–2.35(m,1H),2.07–2.00(m,2H),1.89–1.78(m,1H),1.56–1.39(m,1H).LCMS(ESI)C 33 H 32 ClN 4 O 4 + [M+H] + Calculated 583.21, measured 583.2.
Example 108: preparation of 3- (5- ((5- (4 '-chloro- [1,1' -biphenyl ] -2-carbonyl) -2, 5-diazabicyclo [2.2.2] oct-2-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05543)
The title compound (GT-05543) (white solid, 51mg, 60% yield) was prepared according to the procedure of scheme 1. 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),8.02–7.88(m,1H),7.85–7.76(m,1H),7.68–7.34(m,9H),5.14(dd,J＝12.9,4.7Hz,1H),4.71–4.42(m,3H),4.42–4.28(m,1H),4.25–4.16(m,1H),3.97–3.56(m,2H),3.45–3.41(m,2H),3.27–3.08(m,1H),2.96–2.89(m,2H),2.61(d,J＝16.4Hz,1H),2.47–2.36(m,1H),2.27–2.18(m,1H),2.10–1.94(m,1H),1.80–1.67(m,1H),1.58–1.48(m,1H).LCMS(ESI)C 33 H 32 ClN 4 O 4 + [M+H] + Calculated 583.21, measured 583.2.
Example 109: preparation of 3- (5- (6- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) -2, 6-diazaspiro [3.3] heptane-2-carbonyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05637)
The title compound (GT-05637) (white solid, 21mg, 29% yield) was prepared according to the procedure of scheme 6 and example 76. 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),7.85–7.79(m,2H),7.74–7.63(m,1H),7.64–7.45(m,5H),7.45–7.36(m,2H),7.36–7.29(m,1H),5.13(dd,J＝13.3,5.2Hz,1H),4.52–4.35(m,4H),4.24(brs,3H),4.04(brs,3H),3.64–3.47(m,2H),3.00–2.82(m,1H),2.63(t,J＝16.6Hz,2H),2.46–2.28(m,1H),2.13–1.93(m,1H).LCMS(ESI)C 32 H 30 ClN 4 O 4 + [M+H] + Calculated 569.20, measured 569.3.
Example 110: preparation of 3- (5- (3- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) -3, 8-diazabicyclo [3.2.1] octane-8-carbonyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05638)
Preparation of the target by reference to Synthesis scheme 6 and example 76Compound (GT-05638) (white solid, 42mg, yield 47%). 1 H NMR(400MHz,DMSO-d6)δ11.02(s,1H),7.80(d,J＝7.7Hz,1H),7.56(d,J＝7.8Hz,3H),7.53–7.35(m,7H),5.15(dd,J＝13.2,5.1Hz,1H),4.67(brs,1H),4.54–4.29(m,4H),4.02(brs,1H),3.87(brs,1H),3.03–2.86(m,2H),2.64(t,J＝21.1Hz,2H),2.43(dd,J＝13.1,4.2Hz,1H),2.33–2.15(m,2H),2.08–1.98(m,1H),1.97–1.71(m,3H)LCMS(ESI)C 33 H 32 ClN 4 O 4 + [M+H] + Calculated 583.21, found 583.3.
Example 111: preparation of 3- (5- (8- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) -3, 8-diazabicyclo [3.2.1] octane-3-carbonyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05621)
The title compound (GT-05621) was prepared according to the procedure for synthesis scheme 6 and example 76 (white solid, 31mg, yield 35%). 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),10.66(s,1H),8.06(s,1H),7.78(d,J＝7.7Hz,1H),7.65(s,1H),7.55–7.50(m,5H),7.42(d,J＝8.2Hz,2H),7.36–7.35(m,1H),5.13(dd,J＝13.3,5.0Hz,1H),4.50–4.33(m,3H),4.22(brs,2H),3.96–3.73(m,2H),3.64–3.60(m,1H),3.53–3.45(m,2H),2.98–2.82(m,1H),2.60(d,J＝18.0Hz,1H),2.46–2.31(m,1H),2.04–1.99(m,1H),1.68–1.58(m,1H),1.51–1.42(m,1H),1.24–1.17(m,2H).LCMS(ESI)C 33 H 32 ClN 4 O 4 + [M+H] + Calculated 583.21, measured 583.2.
Example 112: preparation of 3- (5- (5- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) -2, 5-diazabicyclo [2.2.2] octane-2-carbonyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05622)
The title compound (GT-05622) (white solid, 27mg, 30% yield) was prepared according to the procedure of synthesis scheme 6 and example 76. 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),10.39(s,1H),8.00-7.93(m,1H),7.85–7.73(m,1H),7.68–7.27(m,9H),5.14(dd,J＝13.0,4.5Hz,1H),4.60–4.27(m,4H),3.75(brs,1H),3.60–3.37(m,3H),3.18–3.14(m,1H),3.07–2.83(m,2H),2.61(d,J＝16.4Hz,1H),2.41–2.33(m,1H),2.07–1.96(m,2H),1.85–1.79(m,1H),1.69–1.66(m,1H),1.45–1.31(m,1H).LCMS(ESI)C 33 H 32 ClN 4 O 4 + [M+H] + Calculated 583.21, measured 583.2.
Example 113: preparation of 3- (5- (5- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) -2, 5-diazabicyclo [2.2.1] heptane-2-carbonyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05639)
The title compound (GT-05639) was prepared according to the procedure for synthesis scheme 6 and example 76 (white solid, 30mg, 33% yield). 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),8.00–7.84(m,1H),7.79(d,J＝6.9Hz,1H),7.69–7.66(m,1H),7.58–7.49(m,5H),7.40–7.29(m,3H),5.14(dd,J＝13.1,4.6Hz,1H),4.52–4.26(m,5H),3.89–3.67(m,2H),3.60–3.47(m,2H),2.95–2.87(m,2H),2.61(d,J＝15.9Hz,2H),2.47–2.34(m,1H),2.06–1.97(m,2H).LCMS(ESI)C 32 H 30 ClN 4 O 4 + [M+H] + Calculated 569.20, measured 569.2.
Example 114: preparation of 3- (5- ((5- ((4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) methyl) -1-oxo-isoindolin-2-yl) piperidine-2, 6-dione (GT-05398)
The title compound (GT-05398) was prepared according to the method of FIG. 1 (white solid, 22mg, 26% yield). 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),7.91–7.81(m,1H),7.80–7.71(m,1H),7.25–7.11(m,5H),5.14(dd,J＝13.2,5.1Hz,1H),4.55–4.33(m,4H),3.63–3.57(m,1H),3.50–3.45(m,5H),3.22–3.11(m,3H),3.09–3.06(m,2H),2.98–2.80(m,2H),2.61(d,J＝17.1Hz,1H),2.47–2.36(m,2H),2.32–2.27(m,2H),2.03(s,3H),1.55–1.37(m,2H),0.95(s,6H).LCMS(ESI)C 35 H 42 FN 4 O 3 + [M+H] + Calculated 585.32, measured 585.3.
Example 115: preparation of 3- (5- ((3- ((4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-6-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05399)
Preparation of the target Compounds by reference to the method of Synthesis scheme 1Substance (GT-05399) (white solid, 10mg, 12% yield). 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),7.84–7.79(m,1H),7.75–7.59(m,2H),7.18–7.07(m,4H),5.19–5.08(m,1H),4.62–4.50(m,1H),4.49–4.46(m,1H),4.38–4.32(m,3H),3.13–2.80(m,5H),2.61(d,J＝16.6Hz,2H),2.40(dd,J＝17.8,8.7Hz,2H),2.28–2.18(m,4H),2.05–2.00(m,4H),1.42(t,J＝6.4Hz,2H),0.96(d,J＝2.7Hz,6H).LCMS(ESI)C 35 H 40 FN 4 O 3 + [M+H] + Calculated 571.31, found 571.3.
Example 116: preparation of 3- (5- ((3- ((4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -3, 8-diazabicyclo [3.2.1] octane-8-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05400)
The title compound (GT-05400) was prepared according to the method of scheme 1 (white solid, 9mg, yield 11%). 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),7.84(d,J＝9.3Hz,1H),7.74(d,J＝7.9Hz,1H),7.16–7.04(m,5H),5.14(dd,J＝13.1,5.2Hz,1H),4.51–4.47(m,1H),4.42–4.33(m,1H),4.26(d,J＝5.2Hz,1H),3.79(s,2H),2.98–2.85(m,2H),2.83–2.79(m,2H),2.61(d,J＝15.1Hz,3H),2.47–2.39(m,1H),2.26–2.14(m,6H),2.08–1.85(m,6H),1.43–1.40(m,2H),0.94(s,6H).LCMS(ESI)C 35 H 42 FN 4 O 3 + [M+H] + Calculated 585.32, measured 585.3.
Example 117: preparation of 3- (5- ((5- ((4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -2, 5-diazabicyclo [2.2.1] heptane-2-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05401)
The title compound (GT-05401) was prepared according to the method of scheme 1 (white solid, 9mg, 11% yield). 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),8.01–7.54(m,3H),7.26–7.18(m,4H),5.18–5.09(m,1H),4.50–4.33(m,4H),4.22–4.09(m,2H),3.67–3.53(m,2H),3.24–3.10(m,4H),2.99–2.85(m,2H),2.61(d,J＝16.7Hz,1H),2.41–2.26(m,2H),2.26–2.16(m,1H),2.14–1.95(m,4H),1.49–1.45(m,2H),0.96(s,6H).LCMS(ESI)C 34 H 40 FN 4 O 3 + [M+H] + Calculated 571.31, found 571.3.
Example 118: preparation of 3- (5- ((4- (4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05520)
The title compound (GT-05520) was prepared according to the method of scheme 1 (white solid, 11mg, 13% yield). 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),7.80(d,J＝7.7Hz,1H),7.78–7.51(m,2H),7.19–7.11(m,4H),5.14(dd,J＝12.9,4.5Hz,1H),4.51-4.11(m,5H),3.66(d,J＝13.3Hz,1H),3.47–3.45(m,2H),3.22(brs,1H),3.10–3.05(m,1H),2.96–2.88(m,2H),2.61(d,J＝16.3Hz,2H),2.49–2.33(m,3H),2.15(brs,1H),2.07–1.95(m,1H),1.89(d,J＝17.7Hz,1H),1.43(brs,2H),0.96(s,6H).LCMS(ESI)C 33 H 38 FN 4 O 4 + [M+H] + Calculated 573.29, measured 573.3.
Example 119: preparation of 3- (5- ((7- (4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) -2, 7-diazaspiro [3.5] nonan-2-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05404)
The title compound (GT-05404) was prepared according to the method of scheme 1 (white solid, 15mg, yield 18%). 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),7.79–7.76(m,1H),7.71–7.62(m,1H),7.30–7.21(m,2H),7.15–7.09(m,3H),5.13(dd,J＝13.2,5.1Hz,1H),4.55–4.24(m,4H),3.80–3.67(m,3H),3.62–3.47(m,1H),3.17–3.06(m,2H),3.03–2.77(m,3H),2.61(d,J＝18.1Hz,1H),2.40–2.28(m,4H),2.07–1.99(m,2H),1.90(d,J＝17.0Hz,1H),1.75–1.66(m,1H),1.55–1.42(m,3H),1.27–1.20(m,1H),0.98(d,J＝14.6Hz,6H).LCMS(ESI)C 36 H 42 FN 4 O 4 + [M+H] + Calculated 613.32, measured 613.3.
Example 120: preparation of 3- (5- ((5- (4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05405)
Preparation by the method according to FIG. 1The title compound (GT-05405) was prepared (white solid, 12mg, 14% yield). 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),7.92–7.74(m,2H),7.72–7.66(m,1H),7.31(brs,1H),7.28–7.08(m,3H),5.14(dd,J＝13.2,4.9Hz,1H),4.52–4.35(m,4H),3.56–3.43(m,2H),3.21–3.17(m,2H),3.08(d,J＝10.7Hz,1H),2.99–2.86(m,2H),2.76–2.63(m,2H),2.61(d,J＝17.4Hz,2H),2.45–2.41(m,1H),2.33–2.19(m,3H),2.03–1.99(m,2H),1.45–1.42(m,2H),0.99(s,6H).LCMS(ESI)C 35 H 40 FN 4 O 4 + [M+H] + Calculated 599.30, measured 599.3.
Example 121: preparation of 3- (5- ((5- (4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) -2, 5-diazabicyclo [2.2.2] octane-2-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05402)
The title compound (GT-05402) was prepared according to the method of scheme 1 (white solid, 13mg, 16% yield). 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),7.82–7.71(m,2H),7.41–7.09(m,5H),5.16–5.12(m,1H),4.51–4.27(m,5H),3.78–3.66(m,2H),3.12–3.08(m,1H),2.96–2.89(m,2H),2.61(d,J＝15.5Hz,2H),2.43–2.31(m,5H),2.06–1.98(m,2H),1.91–1.73(m,2H),1.57–1.34(m,3H),0.97(s,6H).LCMS(ESI)C 35 H 40 FN 4 O 4 + [M+H] + Calculated 599.30, measured 599.3.
Example 122: preparation of 3- (5- ((5- (4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) -2, 5-diazabicyclo [2.2.1] heptane-2-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05403)
The title compound (GT-05403) was prepared according to the method of scheme 1 (white solid, 13mg, 16% yield). 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),7.81–7.77(M,2H),7.74–7.65(m,1H),7.34–7.09(m,4H),5.14(dd,J＝13.2,4.9Hz,1H),4.53–4.14(m,6H),3.27–3.23(m,2H),3.17–3.13(m,2H),3.05–2.83(m,2H),2.61(d,J＝14.6Hz,1H),2.42(dd,J＝13.1,4.4Hz,1H),2.39–2.12(m,4H),2.09–1.94(m,2H),1.51–1.33(m,2H),0.97(s,6H).LCMS(ESI)C 34 H 38 FN 4 O 4 + [M+H] + Calculated 585.29, measured 585.3.
Example 123: preparation of 3- (5- (4- ((4 '-fluoro-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazine-1-carbonyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05863)
The title compound (GT-05863) (white solid, 25mg, yield 27%) was prepared according to the procedure of synthesis scheme 6 and example 76. 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),10.12(brs,1H),7.79(d,J＝7.8Hz,1H),7.65(s,1H),7.54(d,J＝7.6Hz,1H),7.25–7.19(m,4H),5.14(dd,J＝13.3,5.0Hz,1H),4.51–4.35(m,3H),3.76–3.58(m,8H),2.92–2.89(m,2H),2.68–2.57(m,2H),2.42(dd,J＝13.0,4.2Hz,1H),2.25–2.20(m,3H),2.06–1.96(m,1H),1.69(brs,4H).LCMS(ESI)C 31 H 34 FN 4 O 4 + [M+H] + Calculated 545.26, measured 545.3.
Example 124: preparation of 5- ((4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-05364)
The title compound (GT-05364) (white solid, 24mg, 26% yield) was prepared according to the method of FIG. 1. 1 H NMR(400MHz,DMSO-d6)δ11.14(s,1H),8.10–7.81(m,3H),7.42(d,J＝7.9Hz,2H),7.11(d,J＝7.8Hz,2H),5.16(dd,J＝12.9,5.3Hz,1H),3.31–3.18(m,4H),2.96–2.87(m,4H),2.71–2.54(m,5H),2.26(brs,3H),2.09–2.01(m,4H),1.44(t,J＝6.2Hz,2H),0.95(s,6H).LCMS(ESI)C 33 H 38 ClN 4 O 4 + [M+H] + Calculated 589.26, found 589.3.
Example 125: preparation of 4- ((4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-05365)
The title compound (GT-05365) was prepared according to the method of scheme 1 (white solid, 21mg, yield 24%). 1 H NMR(400MHz,DMSO-d6)δ11.14(s,1H),7.87(brs,3H),7.42(d,J＝8.1Hz,2H),7.12(d,J＝8.4Hz,2H),5.14(dd,J＝12.5,5.4Hz,1H),4.12–3.99(m,1H),3.67–3.51(m,2H),3.40–3.20(m,4H),2.89–2.85(m,3H),2.82–2.68(m,2H),2.63–2.59(m,2H),2.26(brs,2H),2.12–1.90(m,4H),1.46(t,J＝6.0Hz,2H),0.95(s,6H).LCMS(ESI)C 33 H 38 ClN 4 O 4 + [M+H] + Calculated 589.26, found 589.3.
Example 126: preparation of 2- (2, 6-dioxopiperidin-3-yl) -4- ((4- ((4 '-fluoro-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) methyl) isoindoline-1, 3-dione (GT-05862)
The title compound (GT-05862) was prepared according to the method of scheme 1 (white solid, 50mg, 53% yield). 1 H NMR(400MHz,DMSO-d6)δ11.14(s,1H),8.06–7.82(m,3H),7.26–7.12(m,4H),5.15(dd,J＝12.8,5.3Hz,1H),4.49–4.14(m,2H),3.33–3.24(m,4H),3.22–2.97(m,3H),2.97–2.83(m,2H),2.83–2.68(m,2H),2.66–2.56(m,1H),2.54–2.51(m,1H),2.34–2.20(m,4H),2.14–1.98(m,1H),1.68(s,4H).LCMS(ESI)C 31 H 34 FN 4 O 4 + [M+H] + Calculated 545.26, measured 545.3.
Example 127: preparation of 5- ((4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -1, 4-diazepan-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-05397)
The title compound (GT-05397) (white solid, 8mg, yield 10%) was prepared according to the method of FIG. 1. 1 H NMR(400MHz,DMSO-d6)δ11.15(s,1H),8.22–7.95(m,3H),7.45(brs,2H),7.14(d,J＝8.2Hz,2H),5.27–5.12(m,1H),4.65–4.23(m,1H),3.86–3.74(m,1H),3.67–3.43(m,4H),3.29–3.20(m,4H),3.17–2.99(m,2H),2.97–2.77(m,2H),2.62(d,J＝17.8Hz,1H),2.58–2.52(m,1H),2.37–2.17(m,3H),2.14–1.93(m,4H),1.45(t,J＝6.1Hz,2H),0.95(s,6H).LCMS(ESI)C 34 H 40 ClN 4 O 4 + [M+H] + Calculated 603.27, measured 603.3.
Example 128: preparation of 5- ((3- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-6-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-05368)
The title compound (GT-05368) (white solid, 8mg, yield 10%) was prepared according to the method of FIG. 1. 1 H NMR(400MHz,DMSO-d6)δ11.14(s,1H),8.16(brs,1H),8.03(s,1H),8.01(brs,1H),7.39(d,J＝8.3Hz,2H),7.10(t,J＝8.3Hz,2H),5.23–5.14(m,1H),4.49–4.33(m,1H),4.17–4.15(m,1H),3.60–3.47(m,2H),3.13–3.07(m,2H),2.90–2.86(m,3H),2.67–2.58(m,2H),2.57–2.55(m,2H),2.30–2.15(m,3H),2.14–2.03(m,2H),2.00-1.97(m,2H),1.44–1.40(m,2H),0.95(s,6H).LCMS(ESI)C 34 H 38 ClN 4 O 4 + [M+H] + Calculated 601.26, found 601.3.
Example 129: preparation of 5- ((6- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-05532)
The title compound (GT-05532) was prepared according to the method of scheme 1 (white solid, 22mg, yield 25%). 1 H NMR(400MHz,DMSO-d6)δ11.13(s,1H),7.93–7.90(m,2H),7.83–7.63(m,1H),7.53–7.47(m,1H),7.38–7.36(m,1H),7.29–7.12(m,2H),5.17(dd,J＝12.9,3.3Hz,1H),4.09(brs,1H),3.79–3.73(m,2H),3.60–3.48(m,4H),3.07–2.80(m,2H),2.67–2.56(m,3H),2.31–2.10(m,3H),2.11–1.88(m,4H),1.46–1.42(m,2H),0.96(s,6H).LCMS(ESI)C 34 H 38 ClN 4 O 4 + [M+H] + Calculated 601.26, found 601.3.
Example 130: preparation of 5- ((8- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-05537)
The title compound (GT-05537) (white solid, 10mg, yield 35%) was prepared according to the method of scheme 1. 1 H NMR(400MHz,DMSO-d6)δ11.13(s,1H),7.98–7.77(m,3H),7.45(d,J＝8.4Hz,2H),7.19(d,J＝8.4Hz,2H),5.15(dd,J＝12.8,5.4Hz,1H),3.74(d,J＝15.0Hz,4H),3.48(d,J＝4.9Hz,3H),2.96–2.78(m,3H),2.75–2.66(m,2H),2.58–2.51(m,2H),2.34–2.31(m,2H),2.07(s,3H),1.79(d,J＝8.5Hz,2H),1.47(t,J＝6.2Hz,2H),1.21–1.17(m,2H),0.96(s,6H).LCMS(ESI)C 35 H 40 ClN 4 O 4 + [M+H] + Calculated 615.27, measured 615.3.
Example 131: preparation of 5- ((5- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-05533)
The title compound (GT-05533) (white solid, 36mg, yield 42%) was prepared according to the method of FIG. 1. 1 H NMR(400MHz,DMSO-d6)δ11.14(s,1H),8.30–7.73(m,3H),7.47–7.30(m,2H),7.18(d,J＝8.2Hz,2H),5.23–5.12(m,1H),4.45–3.90(m,4H),3.71–3.43(m,6H),3.26–3.02(m,2H),2.95–2.87(m,1H),2.64–2.59(m,2H),2.44–2.40(m,1H),2.31–2.14(m,1H),2.12–1.98(m,3H),1.57–1.37(m,2H),0.96(s,6H).LCMS(ESI)C 34 H 38 ClN 4 O 4 + [M+H] + Calculated 601.26, found 601.3.
Example 132: preparation of 2- (2, 6-dioxopiperidin-3-yl) -5- ((4- ((4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) methyl) isoindoline-1, 3-dione (GT-05395)
The title compound (GT-05395) was prepared according to the method of scheme 1 (white solid, 30mg, 31% yield). 1 H NMR(400MHz,DMSO-d6)δ11.14(s,1H),7.99–7.82(m,3H),7.26–7.04(m,4H),5.16(dd,J＝12.7,5.8Hz,1H),3.62–3.47(m,5H),2.98–2.83(m,4H),2.82–2.70(m,2H),2.67–2.55(m,3H),2.27–2.22(m,2H),2.15–1.95(m,4H),1.45(t,J＝5.0Hz,2H),0.95(s,6H).LCMS(ESI)C 33 H 38 FN 4 O 4 + [M+H] + Calculated 573.29, measured 573.3.
Example 133: preparation of 5- ((4- ((4 '-chloro- [1,1' -biphenyl ] -3-yl) methyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-05630)
The title compound (GT-05630) (white solid, 40mg, yield) was prepared according to the method of FIG. 143％)。 1 H NMR(400MHz,DMSO-d6)δ11.14(s,1H),8.03(brs,1H),7.97–7.91(m,3H),7.76–7.73(m,3H),7.61–7.50(m,4H),5.16(dd,J＝12.8,5.3Hz,1H),4.47–4.27(m,2H),3.37–3.29(m,4H),3.25–3.10(m,4H),2.94–2.86(m,4H),2.70–2.52(m,3H),2.06–1.99(m,1H).LCMS(ESI)C 31 H 30 ClN 4 O 4 + [M+H] + Calculated 557.20, found 557.2.
Example 134: preparation of 5- ((4- ((4 '-chloro- [1,1' -biphenyl ] -4-yl) methyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-05599)
The title compound (GT-05599) was prepared according to the method of scheme 1 (white solid, 42mg, 46% yield). 1 H NMR(400MHz,DMSO-d6)δ11.14(s,1H),8.09(brs,1H),7.98(brs,2H),7.78–7.73(m,4H),7.68(d,J＝7.5Hz,2H),7.54(d,J＝8.6Hz,2H),5.17(dd,J＝12.8,5.4Hz,1H),4.52–4.00(m,4H),3.43–3.34(m,4H),3.31–3.10(m,4H),2.96–2.84(m,1H),2.61(d,J＝18.2Hz,1H),2.52–2.49(m,1H),2.12–1.99(m,1H).LCMS(ESI)C 31 H 30 ClN 4 O 4 + [M+H] + Calculated 557.20, found 557.2.
Example 135: preparation of 5- ((4- ((3- (4-chlorophenyl) pyridin-4-yl) methyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-05731)
The title compound (GT-05731) (white solid, 8mg, 14% yield) was prepared according to the method of FIG. 1. 1 H NMR(400MHz,DMSO-d6)δ11.15(s,1H),8.80(d,J＝5.5Hz,1H),8.69(s,1H),8.22(s,1H),8.11(d,J＝7.6Hz,1H),8.02(d,J＝7.6Hz,2H),7.59(d,J＝8.3Hz,2H),7.52(d,J＝8.2Hz,2H),5.18(dd,J＝12.7,5.4Hz,1H),4.48(s,2H),3.26(brs,4H),3.07(brs,2H),2.96–2.77(m,4H),2.66–2.55(m,3H),2.09–2.05(m,1H).LCMS(ESI)C 30 H 29 ClN 5 O 4 + [M+H] + Calculated 558.19, measured 558.2.
Example 136: preparation of 5- ((4- ([ 2,4' -bipyridyl ] -5-ylmethyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-05634)
The title compound (GT-05634) was prepared according to the method of scheme 1 (white solid, 35mg, 36% yield). 1 H NMR(400MHz,DMSO-d6)δ11.15(s,1H),9.11(s,1H),9.06(d,J＝5.6Hz,2H),8.74(d,J＝5.6Hz,2H),8.53(d,J＝8.1Hz,1H),8.45(d,J＝8.1Hz,1H),8.30(s,1H),8.18(d,J＝7.6Hz,1H),8.02(d,J＝7.6Hz,1H),5.18(dd,J＝12.6,5.3Hz,2H),4.61(brs,8H),4.31(brs,4H),2.94–2.87(m,1H),2.65–2.55(m,2H),2.11–2.03(m,1H).LCMS(ESI)C 29 H 29 N 6 O 4 + [M+H] + Calculated 525.22, measured 525.2.
Example 137: preparation of 2- (2, 6-dioxopiperidin-3-yl) -5- ((4- ((5-phenylpyrazin-2-yl) methyl) piperazin-1-yl) methyl) isoindoline-1, 3-dione (GT-05545)
The title compound (GT-05545) was prepared according to the procedure for synthesis scheme 1 (white solid, 31mg, yield 32%). 1 H NMR(400MHz,DMSO-d6)δ11.14(s,1H),9.30(s,1H),8.88(s,1H),8.18(dd,J＝7.9,1.6Hz,2H),8.12(brs,1H),8.00(brs,2H),7.62–7.49(m,3H),5.17(dd,J＝12.8,5.4Hz,1H),4.37(brs,4H),3.34–3.23(m,4H),3.21–3.04(m,4H),2.95–2.83(m,1H),2.69–2.52(m,2H),2.09–2.05(m,1H).LCMS(ESI)C 29 H 29 N 6 O 4 + [M+H] + Calculated 525.22, measured 525.2.
Example 138: preparation of 5- ((4- ((5- (4-chlorophenyl) thiophen-2-yl) methyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-05626)
The title compound (GT-05626) was prepared according to the method of scheme 1 (white solid, 38mg, 42% yield). 1 H NMR(400MHz,DMSO-d6)δ11.14(s,1H),8.06(brs,1H),7.98(brs,2H),7.67(d,J＝8.5Hz,2H),7.50–7.48(m,3H),7.24(brs,1H),5.17(dd,J＝12.9,5.4Hz,1H),4.72–3.95(m,4H),3.41–3.32(m,4H),3.26–3.17(m,4H),3.12–3.05(m,1H),2.91–2.87(m,1H),2.63–2.55(m,1H),2.12–2.02(m,1H).LCMS(ESI)C 29 H 28 ClN 4 O 4 S + [M+H] + Calculated 563.15, measured 563.2.
Example 139: preparation of 2- (2, 6-dioxopiperidin-3-yl) -5- ((4- ((5- (thiophen-2-yl) furan-2-yl) methyl) piperazin-1-yl) methyl) isoindoline-1, 3-dione (GT-05628)
The title compound (GT-05628) was prepared according to the method of scheme 1 (white solid, 31mg, yield 32%). 1 H NMR(400MHz,DMSO-d6)δ11.14(s,1H),8.08(brs,1H),7.98(s,2H),7.57(d,J＝4.7Hz,1H),7.41(d,J＝3.3Hz,1H),7.13(dd,J＝4.9,3.7Hz,1H),6.79(d,J＝3.0Hz,1H),6.72(s,1H),5.17(dd,J＝12.8,5.4Hz,1H),4.54–4.01(m,4H),3.30–3.23(m,4H),3.09–3.04(m,3H),2.94–2.85(m,2H),2.67–2.57(m,1H),2.57–2.51(m,1H),2.12–1.99(m,1H).LCMS(ESI)C 27 H 26 N 4 NaO 5 S + [M+Na] + Calculated 541.15, measured 541.2.
Example 140: preparation of 5- (4- ((4 '-chloro- [1,1' -biphenyl ] -3-yl) methyl) piperazine-1-carbonyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-05631)
The title compound (GT-05631) (white solid, 38mg, 40% yield) was prepared according to the procedure of synthesis scheme 6 and example 76. 1 H NMR(400MHz,DMSO-d6)δ11.32(s,1H),11.15(s,1H),8.04–7.97(m,3H),7.93(d,J＝7.6Hz,1H),7.77(d,J＝8.4Hz,3H),7.61–7.52(m,4H),5.19(dd,J＝12.8,5.4Hz,1H),4.57(brs,1H),4.40(s,2H),3.72–3.59(m,2H),3.55–3.41(m,2H),3.25–3.15(m,3H),2.91–2.87(m,1H),2.62–2.59(m,1H),2.57–2.52(m,1H),2.13–1.99(m,1H).LCMS(ESI)C 31 H 28 ClN 4 O 5 + [M+H] + Calculated 571.17, measured 571.2.
Example 141: preparation of 5- (4- ((4 '-chloro- [1,1' -biphenyl ] -4-yl) methyl) piperazine-1-carbonyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-05600)
The title compound (GT-05600) (white solid, 39mg, yield 41%) was prepared according to the procedure of synthesis scheme 6 and example 76. 1 H NMR(400MHz,DMSO-d6)δ11.15(s,1H),8.04–7.97(m,2H),7.92(d,J＝7.7Hz,1H),7.79(d,J＝7.2Hz,2H),7.74(d,J＝8.5Hz,2H),7.67(d,J＝6.9Hz,2H),7.55(d,J＝8.5Hz,2H),5.19(dd,J＝12.8,5.4Hz,1H),4.58(brs,1H),4.38(brs,2H),3.76–3.47(m,3H),3.27–3.12(m,4H),2.96–2.84(m,1H),2.62(d,J＝18.8Hz,1H),2.57–2.52(m,1H),2.14–2.00(m,1H).LCMS(ESI)C 31 H 28 ClN 4 O 5 + [M+H] + Calculated 571.17, measured 571.2.
Example 142: preparation of 5- (4- ((3- (4-chlorophenyl) pyridin-4-yl) methyl) piperazine-1-carbonyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-05732)
The title compound (GT-05732) (white solid, 25mg, 44% yield) was prepared according to the procedure of synthesis scheme 6 and example 76. 1 H NMR(400MHz,DMSO-d6)δ11.14(s,1H),8.75(d,J＝5.2Hz,1H),8.60(s,1H),8.12(s,1H),7.99(d,J＝7.7Hz,1H),7.93(s,1H),7.86(d,J＝7.6Hz,1H),7.62(d,J＝7.9Hz,2H),7.48(d,J＝8.1Hz,2H),5.18(dd,J＝12.6,5.3Hz,1H),4.53–4.12(m,3H),3.32–3.22(m,4H),2.96–2.84(m,2H),2.67–2.53(m,4H),2.09–2.04(m,1H).LCMS(ESI)C 30 H 27 ClN 5 O 5 + [M+H] + Calculated 572.17, measured 572.2.
Example 143: preparation of 5- (3- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -3, 8-diazabicyclo [3.2.1] oct-8-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-05375)
The title compound (GT-05375) (white solid, 8mg, 12% yield) was prepared according to the method of FIG. 4. 1 H NMR(400MHz,DMSO-d6)δ11.10(s,1H),7.76(d,J＝8.2Hz,1H),7.34(brs,1H),7.25(d,J＝8.2Hz,2H),7.19–7.17(m,1H),7.06–7.02(m,2H),5.13(dd,J＝13.4,9.5Hz,1H),4.74–4.60(m,2H),4.51–4.47(m,1H),3.12–3.06(m,2H),2.92–2.87(m,2H),2.76–2.72(m,2H),2.67–2.64(m,1H),2.60–2.57(m,1H),2.24–2.16(m,4H),2.10–2.02(m,3H),1.92–1.85(m,2H),1.46–1.35(m,3H),0.88(s,6H).LCMS(ESI)C 34 H 38 ClN 4 O 4 + [M+H] + Calculated 601.26, found 601.3.
Example 144: preparation of 5- (8- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-05376)
The title compound (GT-05376) was prepared according to the method of FIG. 4 (white solid, 3mg, yield 5%). 1 H NMR(400MHz,DMSO-d6)δ11.09(s,1H),7.74(d,J＝8.8Hz,1H),7.48(d,J＝8.3Hz,2H),7.34–7.33(m,1H),7.24(d,J＝8.3Hz,2H),7.22–7.17(m,1H),5.08(dd,J＝12.0,4.7Hz,1H),4.01–3.88(m,3H),3.62–3.60(m,1H),3.50–3.47(m,1H),2.89–2.83(m,3H),2.60–2.51(m,2H),2.39–2.32(m,3H),2.05–1.96(m,3H),1.79–1.75(m,2H),1.52–1.50(m,2H),1.33–1.29(m,2H),1.00(s,6H).LCMS(ESI)C 34 H 38 ClN 4 O 4 + [M+H] + Calculated 601.26, found 601.3.
Example 145: preparation of 5- (3- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptane-6-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-05377)
The title compound (GT-05377) was prepared according to the method of FIG. 4 (white solid, 11mg, 16% yield). 1 H NMR(400MHz,DMSO-d6)δ11.11(s,1H),7.71(d,J＝8.3Hz,1H),7.18(d,J＝7.4Hz,2H),7.04(s,1H),6.95(d,J＝8.2Hz,2H),6.78(d,J＝6.7Hz,1H),5.15(dd,J＝12.6,5.7Hz,1H),4.61–4.47(m,2H),3.55–3.50(m,2H),3.14–3.06(m,2H),2.98–2.85(m,2H),2.76–2.71(m,1H),2.70–2.56(m,3H),2.44(d,J＝9.7Hz,2H),2.24–2.19(m,2H),2.11–2.02(m,2H),1.41–1.38(m,2H),0.92(s,6H).LCMS(ESI)C 33 H 36 ClN 4 O 4 + [M+H] + Calculated 587.24, measured 587.3.
Example 146: preparation of 5- (6- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-05378)
The title compound (GT-05378) was prepared according to the method of FIG. 4 (white solid, 3mg, yield 5%). 1 H NMR(400MHz,DMSO-d6)δ11.09(s,1H),7.79(d,J＝8.5Hz,1H),7.73(d,J＝4.5Hz,1H),7.51(d,J＝8.4Hz,1H),7.25(d,J＝8.2Hz,1H),7.20–7.18(m,1H),7.05–7.02(m,1H),6.83–6.81(m,1H),5.13–5.08(m,1H),4.57–4.49(m,1H),4.02–3.95(m,1H),3.92–3.88(m,1H),3.82–3.72(m,1H),3.51–3.49(m,1H),3.02–2.87(m,3H),2.57–2.51(m,3H),2.28–2.23(m,2H),2.07–2.01(m,3H),1.91–1.88(m,1H),1.51–1.38(m,3H),0.96(s,6H).LCMS(ESI)C 33 H 36 ClN 4 O 4 + [M+H] + Calculated 587.24, measured 587.3.
Example 147: preparation of 5- (5- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -2, 5-diazabicyclo [2.2.2] oct-2-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-05379)
The title compound (GT-05379) was prepared according to the method of FIG. 4 (white solid, 3mg, yield 5%). 1 H NMR(400MHz,DMSO-d6)δ11.07(s,1H),7.67(d,J＝8.7Hz,1H),7.50(d,J＝8.3Hz,1H),7.22–7.16(m,3H),7.07–7.05(m,2H),5.15–5.03(m,1H),4.50–4.39(m,1H),3.71–3.67(m,3H),3.55–3.53(m,2H),3.14-3.09(m,1H),2.98–2.84(m,3H),2.62–2.58(m,2H),2.30–2.23(m,2H),2.05–2.00(m,3H),1.94–1.85(m,2H),1.54–1.43(m,3H),0.96(s,6H).LCMS(ESI)C 34 H 38 ClN 4 O 4 + [M+H] + Calculated 601.26, found 601.3.
Example 148: preparation of 5- (3- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) -3, 8-diazabicyclo [3.2.1] oct-8-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-05370)
The title compound (GT-05370) (white solid, 5mg, yield 8%) was prepared according to the method of FIG. 2. 1 H NMR(400MHz,DMSO-d6)δ11.07(s,1H),7.64–7.60(m,1H),7.48–7.40(m,3H),7.43–7.31(m,3H),7.31–7.15(m,3H),7.11–7.04(m,1H),5.18–5.00(m,1H),4.63–4.58(m,1H),4.49–4.45(m,1H),4.20–4.16(m,1H),3.34–3.29(m,2H),3.06-3.01(m,1H),2.95–2.82(m,1H),2.71–2.55(m,2H),2.35–2.31(m,1H),2.23–2.17(m,2H),2.12–1.94(m,2H),1.83–1.78(m,1H),1.68–1.63(m,1H).LCMS(ESI)C 32 H 30 ClN 4 O 4 + [M+H] + Calculated 569.20, measured 569.2.
Example 149: preparation of 5- (8- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-05371)
The title compound (GT-05371) was prepared according to the method of scheme 2 (white solid, 8mg, 13% yield). 1 H NMR(400MHz,DMSO-d6)δ11.08(s,1H),8.10-8.08(m,1H),7.71(d,J＝8.6Hz,1H),7.60–7.56(m,4H),7.52–7.45(m,2H),7.43–7.36(m,1H),7.31(s,1H),7.19–7.12(m,1H),5.09–5.05(m,1H),4.30(d,J＝5.1Hz,2H),3.91–3.88(m,3H),3.50–3.47(m,2H),3.01–2.81(m,2H),2.62–2.51(m,2H),2.07–1.95(m,1H),1.77(d,J＝8.4Hz,2H),1.40–1.35(m,2H).LCMS(ESI)C 32 H 30 ClN 4 O 4 + [M+H] + Calculated 569.20, measured 569.2.
Example 150: preparation of 5- (3- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptane-6-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-05372)
The title compound (GT-05372) was prepared according to the method of scheme 2 (white solid, 11mg, 17% yield). 1 H NMR(400MHz,DMSO-d6)δ11.14(s,2H),7.87–7.77(m,1H),7.64(d,J＝8.2Hz,1H),7.42(d,J＝7.6Hz,2H),7.29–7.21(m,4H),7.15(d,J＝7.5Hz,1H),6.90(s,1H),6.72–6.60(m,1H),5.21–5.16(m,1H),4.51–4.42(m,2H),4.19–4.02(m,2H),3.29–3.19(m,2H),3.15–3.09(m,2H),3.02–2.85(m,2H),2.72-2.66(m,2H),2.38(d,J＝9.5Hz,1H),2.15–2.02(m,1H).LCMS(ESI)C 31 H 28 ClN 4 O 4 + [M+H] + Calculated 555.18, measured 555.2.
Example 151: preparation of 5- (6- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptane-3-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-05373)
The title compound (GT-05373) was prepared according to the method of scheme 2 (white solid, 11mg, 17% yield). 1 H NMR(400MHz,DMSO-d6)δ11.10(s,1H),8.01-7.99(m,1H),7.73–7.68(m,1H),7.55–7.50(m,2H),7.37–7.34(m,1H),7.25(d,J＝8.4Hz,2H),7.13(d,J＝8.3Hz,2H),6.81(brs,2H),5.14(dd,J＝12.5,5.4Hz,1H),4.49–4.44(m,2H),4.13–4.09(m,2H),3.95(dd,J＝35.8,12.3Hz,1H),3.76(d,J＝12.9Hz,2H),3.05–2.82(m,3H),2.60–2.51(m,2H),2.06–2.01(m,1H),1.93–1.87(m,1H).LCMS(ESI)C 31 H 28 ClN 4 O 4 + [M+H] + Calculated 555.18, measured 555.2.
Example 152: preparation of 5- (5- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) -2, 5-diazabicyclo [2.2.2] oct-2-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-05374)
The title compound (GT-05374) (white solid, 5mg, yield 8%) was prepared according to the method of FIG. 2. 1 H NMR(400MHz,DMSO-d6)δ11.08(s,1H),7.72–7.65(m,1H),7.62–7.58(m,2H),7.57–7.53(m,2H),7.49–7.41(m,2H),7.41–7.30(m,3H),6.95–6.92(m,1H),5.12–5.05(m,1H),4.50–4.31(m,2H),3.55–3.53(m,1H),3.48–3.42(m,2H),3.03–2.80(m,4H),2.67–2.53(m,2H),2.06–1.94(m,1H),1.94–1.69(m,2H),0.96–0.92(m,2H).LCMS(ESI)C 32 H 30 ClN 4 O 4 + [M+H] + Calculated 569.20, measured 569.2.
Example 153: preparation of 2- (2, 6-dioxopiperidin-3-yl) -5- (3- ((4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -3, 8-diazabicyclo [3.2.1] octane-8-yl) isoindoline-1, 3-dione (GT-05384)
The title compound (GT-05384) was prepared according to the method of FIG. 4 (white solid, 10mg, 15% yield). 1 H NMR(400MHz,DMSO-d6)δ11.11(s,1H),7.75(d,J＝8.6Hz,1H),7.34(s,1H),7.18(d,J＝8.2Hz,1H),7.07-7.02(m,4H),5.14(dd,J＝12.8,5.3Hz,1H),4.66(brs,2H),4.49(brs,1H),3.11–3.02(m,2H),2.90–2.85(m,2H),2.77–2.72(m,2H),2.68–2.63(m,1H),2.62–2.55(m,2H),2.21–2.14(m,3H),2.09–2.04(m,2H),1.89–1.86(m,2H),1.43–1.36(m,3H),0.87(s,6H).LCMS(ESI)C 34 H 38 FN 4 O 4 + [M+H] + Calculated 585.29, measured 585.3.
Example 154: preparation of 2- (2, 6-dioxopiperidin-3-yl) -5- (8- ((4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -3, 8-diazabicyclo [3.2.1] octane-3-yl) isoindoline-1, 3-dione (GT-05385)
The title compound (GT-05385) was prepared according to the method of FIG. 4 (white solid, 6mg, 9% yield). 1 H NMR(400MHz,DMSO-d6)δ11.09(s,1H),7.77–7.72(m,1H),7.34–7.33(m,1H),7.26–7.24(m,3H),7.21–7.19(m,2H),5.09(dd,J＝13.3,6.4Hz,1H),3.97–3.90(m,3H),3.60–3.54(m,1H),3.53–3.50(m,2H),2.91–2.85(m,2H),2.62–2.57(m,2H),2.41–2.33(m,2H),2.15–2.11(m,2H),2.05–1.95(m,4H),1.81–1.71(m,2H),1.53–1.50(m,2H),1.32–1.26(m,2H),1.00(s,6H).LCMS(ESI)C 34 H 38 FN 4 O 4 + [M+H] + Calculated 585.29, measured 585.3.
Example 155: preparation of 2- (2, 6-dioxopiperidin-3-yl) -5- (3- ((4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptane-6-yl) isoindoline-1, 3-dione (GT-05386)
The title compound (GT-05386) was prepared according to the method of FIG. 4 (white solid, 12mg, 19% yield). 1 H NMR(400MHz,DMSO-d6)δ11.12(s,1H),7.66(d,J＝8.1Hz,1H),7.03–6.93(m,5H),6.76(dd,J＝8.3,1.4Hz,1H),5.14(d,J＝3.4Hz,1H),4.61–4.50(m,2H),3.59–3.49(m,2H),3.15–3.01(m,3H),2.93–2.88(m,2H),2.78–2.72(m,1H),2.67–2.62(m,1H),2.40–2.33(m,2H),2.23–2.18(m,2H),2.14–2.02(m,2H),1.98(brs,2H),1.44–1.36(m,2H),0.93(s,6H).LCMS(ESI)C 33 H 36 FN 4 O 4 + [M+H] + Calculated 571.27, found 571.3.
Example 156: preparation of 2- (2, 6-dioxopiperidin-3-yl) -5- (6- ((4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) isoindoline-1, 3-dione (GT-05387)
The title compound (GT-05387) was prepared according to the method of FIG. 4 (white solid, 10mg, 16% yield). 1 H NMR(400MHz,DMSO-d6)δ11.09(s,1H),7.28–7.09(m,5H),6.92–6.74(m,2H),5.10(dd,J＝14.8,10.2Hz,1H),4.59–4.48(m,1H),4.05–3.73(m,3H),2.99–2.87(m,4H),2.60–2.55(m,1H),2.31–2.24(m,2H),2.09–1.82(m,6H),1.51–1.42(m,3H),0.97(s,6H).LCMS(ESI)C 33 H 36 FN 4 O 4 + [M+H] + Calculated 571.27, found 571.3.
Example 157: preparation of 2- (2, 6-dioxopiperidin-3-yl) -5- (5- ((4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -2, 5-diazabicyclo [2.2.2] octane-2-yl) isoindoline-1, 3-dione (GT-05388)
The title compound (GT-05388) was prepared according to the method of FIG. 4 (white solid, 3mg, yield 5%). 1 H NMR(400MHz,DMSO-d6)δ11.08(s,1H),7.72–7.65(m,1H),7.30–7.16(m,2H),7.10–7.07(m,2H),7.01–6.92(m,2H),5.13–5.04(m,1H),4.46–4.42(m,1H),3.76–3.60(m,3H),3.29–3.20(m,3H),3.13–3.03(m,1H),3.00–2.83(m,2H),2.65–2.53(m,3H),2.33–2.25(m,2H),2.10–1.96(m,3H),1.92–1.86(m,2H),1.49–1.44(m,2H),0.96(s,6H).LCMS(ESI)C 34 H 38 FN 4 O 4 + [M+H] + Calculated 585.29, measured 585.3.
Example 158: preparation of 3- (5- ((3- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -3, 8-diazabicyclo [3.2.1] octane-8-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05494)
The title compound (GT-05494) was prepared according to the method of scheme 1 (white solid, 34mg, yield 37.88%). 1 H NMR(400MHz,DMSO-d6)δ11.03(s,1H),10.21(s,1H),8.07(d,J＝5.7Hz,1H),7.66(d,J＝8.6Hz,1H),7.38(t,J＝8.4Hz,2H),7.07(d,J＝7.9Hz,2H),5.14(dd,J＝13.3,5.1Hz,1H),4.55–4.19(m,4H),3.94(s,2H),3.63(s,3H),3.59–3.53(m,2H),3.00–2.86(m,2H),2.61(d,J＝16.5Hz,2H),2.46–2.39(m,1H),2.26(s,4H),2.01(dd,J＝15.1,8.3Hz,4H),1.43(t,J＝6.2Hz,2H),0.94(s,6H).LCMS(ESI)C 35 H 41 ClFN 4 O 3 + [M+H] + Calculated, 619.29, found 619.3.
Example 159: preparation of 3- (5- ((3- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -3, 8-diazabicyclo [3.2.1] octane-8-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05495)
The title compound (GT-05495) was prepared according to the method of scheme 1 (white solid, 21mg, 23.40% yield). 1 H NMR(400MHz,DMSO-d6)δ11.02(s,1H),10.33(s,1H),7.73(s,2H),7.37(d,J＝8.2Hz,2H),7.08(s,2H),5.10(dd,J＝13.3,5.1Hz,1H),4.45(d,J＝33.3Hz,2H),4.25(s,2H),3.77(d,J＝34.5Hz,2H),3.64(s,3H),2.99–2.71(m,3H),2.63(t,J＝17.6Hz,2H),2.41(ddd,J＝26.0,13.1,4.2Hz,2H),2.22(s,4H),1.97(s,4H),1.42(s,2H),0.94(s,6H).LCMS(ESI)C 35 H 41 ClFN 4 O 3 + [M+H] + Calculated 619.29, found 619.3.
Example 160: preparation of 3- (6- ((3- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -3, 8-diazabicyclo [3.2.1] octane-8-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05459)
The title compound (GT-05459) was prepared according to the method of scheme 1 (white solid, 15mg, yield GT-05459%). 1 H NMR(400MHz,DMSO)δ11.01(s,1H),9.90(s,1H),8.00(d,J＝12.8Hz,1H),7.90(d,J＝7.7Hz,1H),7.70(d,J＝7.8Hz,1H),7.38(t,J＝10.4Hz,2H),7.07(t,J＝10.6Hz,2H),5.13(dd,J＝13.3,5.1Hz,1H),4.44(dd,J＝51.7,17.7Hz,2H),4.27(s,2H),3.77(s,2H),3.44(d,J＝7.1Hz,2H),2.90(ddd,J＝38.4,21.8,15.1Hz,3H),2.61(d,J＝17.1Hz,2H),2.42(dd,J＝13.2,4.7Hz,1H),2.22(d,J＝26.8Hz,4H),1.99(dd,J＝14.1,7.2Hz,4H),1.42(t,J＝6.2Hz,2H),0.94(d,J＝5.6Hz,6H).LCMS(ESI)C 35 H 42 ClN 4 O 3 + [M+H] + Calculated 601.29, found 601.3.
Example 161: preparation of 5- ((3- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -3, 8-diazabicyclo [3.2.1] octane-8-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-04719)
The title compound (GT-04719) was prepared according to the method of scheme 1 (white solid, 21mg, yield 58.87%). 1 H NMR(400MHz,DMSO)δ11.14(s,1H),10.17(s,1H),8.25(s,1H),8.15(d,J＝7.7Hz,1H),8.02(d,J＝7.7Hz,1H),7.37(d,J＝8.2Hz,2H),7.05(d,J＝8.1Hz,2H),5.18(dd,J＝12.7,5.3Hz,1H),4.35(s,2H),3.79(s,2H),3.45(s,2H),2.97–2.75(m,3H),2.60(t,J＝15.5Hz,3H),2.35(d,J＝16.3Hz,2H),2.21(d,J＝20.3Hz,4H),2.10–2.04(m,1H),1.97(s,3H),1.42(t,J＝6.3Hz,2H),0.94(s,6H).LCMS(ESI)C 35 H 40 ClN 4 O 4 + [M+H] + Calculated 615.27, measured 615.3.
Example 162: preparation of 3- (5- ((5- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -2, 5-diazabicyclo [2.2.2] octane-2-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05460)
The title compound (GT-05460) was prepared according to the method of scheme 1 (white solid, 8mg, 17.83% yield). 1 H NMR(400MHz,DMSO)δ11.02(s,1H),8.04–7.35(m,4H),7.19(d,J＝7.6Hz,2H),5.14(dd,J＝12.8,4.5Hz,1H),4.56–4.35(m,2H),3.75(s,7H),3.17(s,2H),2.91(dd,J＝21.6,8.9Hz,2H),2.61(d,J＝16.7Hz,1H),2.37(d,J＝33.4Hz,5H),2.05(d,J＝20.6Hz,4H),1.80(d,J＝36.2Hz,1H),1.46(s,3H),0.96(s,6H).LCMS(ESI)C 35 H 41 ClFN 4 O 3 + [M+H] + Calculated 619.29, found 619.3.
Example 163: preparation of 3- (5- ((5- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -2, 5-diazabicyclo [2.2.2] octane-2-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05781)
The title compound (GT-05781) was prepared according to the method of scheme 1 (white solid, 28mg, yield 39.00%). 1 H NMR(400MHz,DMSO-d6)δ11.02(s,1H),7.37(dd,J＝139.8,48.1Hz,6H),5.10(dd,J＝13.2,4.6Hz,1H),4.55–4.37(m,2H),3.75(s,10H),3.04–2.87(m,2H),2.61(d,J＝17.8Hz,1H),2.46–2.23(m,4H),2.05(d,J＝17.5Hz,4H),1.64–1.30(m,3H),0.96(s,6H).LCMS(ESI)C 35 H 41 ClFN 4 O 3 + [M+H] + Calculated 619.29, found 619.3.
Example 164: preparation of 3- (4- ((5- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -2, 5-diazabicyclo [2.2.2] octane-2-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05461)
The title compound (GT-05461) was prepared according to the method of scheme 1 (white solid, 18mg, yield 41.31%). 1 H NMR(400MHz,DMSO)δ11.04(s,1H),7.75(s,1H),7.58(s,1H),7.49–7.08(m,5H),5.17(s,1H),4.48(s,2H),3.88–3.43(m,9H),2.93(dd,J＝21.6,9.1Hz,2H),2.70–2.57(m,2H),2.33(s,4H),2.02(s,4H),1.46(s,3H),0.96(s,6H).LCMS(ESI)C 35 H 42 ClN 4 O 3 + [M+H] + Calculated 601.29, found 601.3.
Example 165: preparation of 3- (6- ((5- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -2, 5-diazabicyclo [2.2.2] octane-2-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05485)
The title compound (GT-05485) was prepared according to the method of scheme 1 (white solid, 5mg, yield 9.56%). 1 H NMR(400MHz,DMSO)δ11.00(s,1H),8.10–7.60(m,3H),7.43(s,2H),7.18(d,J＝7.4Hz,2H),5.12(d,J＝8.1Hz,1H),4.61–4.29(m,4H),3.45(d,J＝7.0Hz,9H),2.91(s,2H),2.61(d,J＝17.1Hz,1H),2.42(d,J＝13.0Hz,1H),2.26(s,2H),2.12–1.86(m,4H),1.45(s,3H),0.95(s,6H).LCMS(ESI)C 35 H 42 ClN 4 O 3 + [M+H] + Calculated 601.29, measured 602.3.
Example 166: preparation of 5- ((5- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -2, 5-diazabicyclo [2.2.2] octane-2-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-05463)
The title compound (GT-05463) was prepared according to the method of scheme 1 (white solid, 15mg, yield 33.64%). 1 H NMR(400MHz,DMSO)δ11.15(s,1H),8.41–8.07(m,1H),7.97(s,1H),7.90–7.74(m,1H),7.42(d,J＝20.2Hz,2H),7.18(d,J＝7.7Hz,2H),5.28–5.13(m,1H),4.69(s,2H),3.94–3.45(m,7H),2.90(dd,J＝21.9,9.7Hz,2H),2.59(dd,J＝24.5,14.6Hz,3H),2.35–1.91(m,7H),1.46(s,3H),0.96(s,6H).LCMS(ESI)C 35 H 40 ClN 4 O 4 + [M+H] + Calculated 615.27, measured 615.3.
Example 167: preparation of 3- (4-fluoro-5- ((4- ((4 '-fluoro-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05466)
The title compound (GT-05466) was prepared according to the method of scheme 1 (white solid, 18mg, yield 36.01%). 1 H NMR(400MHz,DMSO)δ11.03(s,1H),7.75(s,1H),7.69–7.62(m,1H),7.29–7.11(m,4H),5.14(dd,J＝13.3,5.1Hz,1H),4.59–4.39(m,2H),4.23(s,2H),3.56(s,3H),3.33–3.06(m,5H),2.91(ddd,J＝32.4,18.9,12.0Hz,3H),2.61(d,J＝17.4Hz,1H),2.46(dd,J＝13.2,4.6Hz,1H),2.27(d,J＝26.9Hz,4H),2.06–1.96(m,1H),1.68(s,4H).LCMS(ESI)C 31 H 35 F 2 N 4 O 3 + [M+H] + Calculated 549.27, measured 549.3.
Example 168: preparation of 3- (6- ((4- ((4 '-fluoro-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05465)
The title compound (GT-05465) was prepared according to the method of scheme 1 (white solid, 13mg, yield 26.89%). 1 H NMR(400MHz,DMSO)δ11.01(s,1H),7.95(s,1H),7.82(d,J＝7.7Hz,1H),7.70(d,J＝7.8Hz,1H),7.18(p,J＝8.8Hz,4H),5.13(dd,J＝13.3,5.0Hz,1H),4.44(dd,J＝52.5,17.8Hz,4H),3.60(dd,J＝8.6,4.7Hz,7H),3.01–2.79(m,3H),2.61(d,J＝17.4Hz,1H),2.55–2.52(m,1H),2.42(dd,J＝13.1,4.7Hz,1H),2.26(d,J＝25.5Hz,4H),2.09–1.94(m,1H),1.67(s,4H).LCMS(ESI)C 31 H 36 FN 4 O 3 + [M+H] + Calculated 531.28, measured 531.3.
Example 169: preparation of 2- (2, 6-dioxopiperidin-3-yl) -5- ((4- ((4 '-fluoro-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) methyl) isoindoline-1, 3-dione (GT-05464)
The title compound (GT-05464) was prepared according to the method of scheme 1 (white solid, 21mg, 42.32% yield). 1 H NMR(400MHz,DMSO)δ11.15(s,1H),8.12(s,1H),7.99(t,J＝6.5Hz,2H),7.24–7.12(m,4H),5.18(dd,J＝12.8,5.4Hz,1H),4.33(s,2H),3.52(s,3H),3.17(s,6H),2.96–2.84(m,2H),2.58(dd,J＝24.1,12.4Hz,2H),2.27(d,J＝26.4Hz,4H),2.11–2.03(m,1H),1.68(s,4H).LCMS(ESI)C 31 H 34 FN 4 O 4 + [M+H] + Calculated 545.26, measured 545.3.
Example 170: preparation of 3- (4-fluoro-5- ((4- (4 '-fluoro-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05472)
The title compound (GT-05472) was prepared according to the method of scheme 1 (white solid, 37mg, yield 47.41%). 1 H NMR(400MHz,DMSO)δ11.04(s,1H),7.85(s,1H),7.67(d,J＝7.7Hz,1H),7.17(d,J＝45.8Hz,4H),5.16(dd,J＝12.5,4.3Hz,1H),4.69–4.30(m,4H),3.70(s,6H),3.34(s,1H),3.18–2.89(m,3H),2.62(d,J＝15.7Hz,2H),2.37(s,1H),2.18–1.99(m,3H),1.67(d,J＝30.3Hz,4H).LCMS(ESI)C 31 H 33 F 2 N 4 O 4 + [M+H] + Calculated 563.25, measured 563.3.
Example 171: preparation of 3- (6-fluoro-5- ((4- (4 '-fluoro-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05473)
The title compound (GT-05473) was prepared according to the method of scheme 1 (white solid, 25mg, yield 32.03%). 1 H NMR(400MHz,DMSO)δ11.72(s,1H),11.03(s,1H),10.82(s,1H),7.86(d,J＝30.8Hz,1H),7.66(d,J＝8.4Hz,1H),7.17(d,J＝43.3Hz,4H),5.13(s,1H),4.41(dd,J＝50.4,17.4Hz,5H),3.74(s,1H),3.38–3.24(m,4H),2.92(s,4H),2.61(d,J＝16.4Hz,2H),2.42(s,1H),2.04(dd,J＝22.4,15.1Hz,3H),1.71(s,4H).LCMS(ESI)C 31 H 33 F 2 N 4 O 4 + [M+H] + Calculated 563.25, measured 563.3.
Example 172: preparation of 3- (7-fluoro-5- ((4- (4 '-fluoro-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05474)
Method according to scheme 1The title compound (GT-05474) was prepared (white solid, 31mg, yield 39.72%). 1 H NMR(400MHz,DMSO)δ12.12(s,1H),11.53(s,1H),11.03(s,1H),7.57(d,J＝27.2Hz,2H),7.31–6.99(m,4H),5.11(dd,J＝13.5,4.3Hz,1H),4.58–4.32(m,4H),3.86–3.67(m,4H),3.13(dd,J＝48.6,14.1Hz,2H),2.97–2.87(m,2H),2.71(d,J＝2.8Hz,1H),2.61(d,J＝18.3Hz,2H),2.40(dd,J＝13.7,6.9Hz,1H),2.23–1.95(m,4H),1.68(d,J＝30.3Hz,4H).LCMS(ESI)C 31 H 33 F 2 N 4 O 4 + [M+H] + Calculated 563.25, measured 563.3.
Example 173: preparation of 3- (6- ((4- (4 '-fluoro-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05470)
The title compound (GT-05470) was prepared according to the method of scheme 1 (white solid, 15mg, yield 19.85%). 1 H NMR(400MHz,DMSO)δ11.87(s,1H),11.13(s,1H),11.01(s,1H),7.99–7.67(m,3H),7.14(dd,J＝45.3,23.5Hz,4H),5.13(d,J＝13.0Hz,1H),4.54–4.30(m,4H),3.84–3.71(m,5H),3.41(d,J＝70.1Hz,1H),3.12(d,J＝49.7Hz,2H),2.98–2.87(m,2H),2.65(d,J＝14.2Hz,1H),2.40(d,J＝19.0Hz,1H),2.19–1.97(m,4H),1.67(d,J＝32.1Hz,4H).LCMS(ESI)C 31 H 34 FN 4 O 4 + [M+H] + Calculated 545.26, measured 545.3.
Example 174: preparation of 3- (4- ((4- (4 '-fluoro-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05471)
The title compound (GT-05471) was prepared according to the method of scheme 1 (white solid, 26mg, 34.41% yield). 1 H NMR(400MHz,DMSO)δ12.01(s,1H),11.31(s,1H),11.07(s,1H),7.99–7.74(m,2H),7.61(t,J＝7.5Hz,1H),7.30–7.07(m,4H),5.16(dd,J＝8.7,4.5Hz,1H),4.82(d,J＝19.6Hz,1H),4.63–4.18(m,5H),3.88(s,2H),3.50(s,2H),3.31–2.91(m,5H),2.73–2.66(m,1H),2.38–2.32(m,1H),2.07(d,J＝21.6Hz,3H),1.68(d,J＝30.9Hz,4H).LCMS(ESI)C 31 H 34 FN 4 O 4 + [M+H] + Calculated value 545.26, found 545.3.
Example 175: preparation of 2- (2, 6-dioxopiperidin-3-yl) -5- ((4- (4 '-fluoro-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) piperazin-1-yl) methyl) isoindoline-1, 3-dione (GT-05468)
The title compound (GT-05468) was prepared according to the method of FIG. 1 (white solid, 35mg, yield 45.17%). 1 H NMR(400MHz,DMSO)δ11.94(s,1H),11.15(s,1H),8.06(d,J＝42.6Hz,3H),7.17(d,J＝40.3Hz,4H),5.17(dd,J＝15.0,10.4Hz,1H),4.38(d,J＝70.8Hz,3H),3.75(s,1H),3.41(s,2H),3.12(d,J＝40.6Hz,5H),2.98–2.86(m,2H),2.62(d,J＝17.4Hz,2H),2.35(d,J＝15.5Hz,1H),2.13–1.95(m,3H),1.67(d,J＝30.0Hz,4H).LCMS(ESI)C 31 H 32 FN 4 O 5 + [M+H] + Calculated 559.24, measured 559.3.
Example 176: preparation of 3- (4-fluoro-5- ((3- (4 '-fluoro-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) -3, 6-diazabicyclo [3.1.1] heptane-6-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05475)
The title compound (GT-05475) (white solid, mg, yield%) was prepared according to the method of scheme 1. 1 H NMR(400MHz,DMSO)δ11.02(s,1H),7.97–7.57(m,2H),7.31(dd,J＝39.5,22.3Hz,2H),7.15(dd,J＝19.0,10.2Hz,2H),5.18–5.09(m,1H),4.83–4.02(m,6H),3.90–3.41(m,3H),3.33–2.87(m,4H),2.61(d,J＝16.8Hz,2H),2.46–2.33(m,2H),2.18–2.00(m,3H),1.72(s,4H).LCMS(ESI)C 32 H 33 F 2 N 4 O 4 + [M+H] + Calculated 575.25, measured 575.3.
Example 177: preparation of 3- (6-fluoro-5- ((3- (4 '-fluoro-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) -3, 6-diazabicyclo [3.1.1] heptane-6-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05476)
The title compound (GT-05476) was prepared according to the method of scheme 1 (white solid, 25mg, yield 29.04%). 1 H NMR(400MHz,DMSO)δ11.02(s,1H),10.05(d,J＝219.9Hz,1H),7.37(qdd,J＝71.3,62.4,54.4Hz,6H),5.13(dd,J＝9.2,3.8Hz,1H),4.79–3.92(m,5H),3.81–3.45(m,2H),3.14(s,4H),2.93(dd,J＝21.8,8.6Hz,1H),2.61(d,J＝15.7Hz,2H),2.47–2.25(m,3H),2.07(d,J＝17.1Hz,3H),1.72(s,4H).LCMS(ESI)C 32 H 33 F 2 N 4 O 4 + [M+H] + Calculated 575.25, measured 575.3.
Example 178: preparation of 3- (7-fluoro-5- ((3- (4 '-fluoro-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) -3, 6-diazabicyclo [3.1.1] heptane-6-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05477)
The title compound (GT-05477) was prepared according to the method of scheme 1 (white solid, 21mg, yield 27.44%). 1 H NMR(400MHz,DMSO)δ11.62(s,1H),11.02(s,1H),9.74(s,1H),7.79–7.43(m,2H),7.38–7.02(m,4H),5.09(dd,J＝13.2,4.9Hz,1H),4.88–4.00(m,6H),3.98–3.38(m,4H),3.32–2.85(m,4H),2.65–2.54(m,2H),2.33(s,1H),2.07(dd,J＝30.9,6.6Hz,3H),1.72(s,4H).LCMS(ESI)C 32 H 33 F 2 N 4 O 4 + [M+H] + Calculated 575.25, measured 575.3.
Example 179: preparation of 3- (4- ((3- (4 '-fluoro-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) -3, 6-diazabicyclo [3.1.1] heptan-6-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05478)
The title compound (GT-05478) was prepared according to the method of scheme 1 (white solid, 32mg, yield 38.37%). 1 H NMR(400MHz,DMSO-d6)δ11.03(d,J＝20.3Hz,1H),9.50(s,1H),8.01–6.97(m,7H),5.19(s,1H),4.91–4.01(m,5H),3.74(s,4H),3.22–2.87(m,2H),2.79–2.53(m,3H),2.40(d,J＝15.7Hz,3H),2.07(d,J＝22.4Hz,3H),1.72(s,4H).LCMS(ESI)C 32 H 34 FN 4 O 4 + [M+H] + Calculated 557.26, measured 557.3.
Example 180: preparation of 3- (6- ((3- (4 '-fluoro-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) -3, 6-diazabicyclo [3.1.1] heptan-6-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05479)
The title compound (GT-05479) was prepared according to the method of scheme 1 (white solid, 15mg, 17.96% yield). 1 H NMR(400MHz,DMSO)δ11.39(s,1H),11.01(s,1H),9.55(s,1H),8.01–7.84(m,1H),7.73–7.61(m,1H),7.47(s,1H),7.38–7.15(m,4H),5.12(dd,J＝13.3,5.0Hz,1H),4.84–4.11(m,6H),4.12–3.78(m,2H),3.66(d,J＝53.4Hz,3H),3.30–3.06(m,2H),2.96–2.86(m,1H),2.63(s,1H),2.41(dd,J＝12.9,4.3Hz,1H),2.10(dd,J＝68.6,38.6Hz,4H),1.72(s,4H).LCMS(ESI)C 32 H 34 FN 4 O 4 + [M+H] + Calculated 557.26, measured 557.3.
Example 181: preparation of 3- (7- ((3- (4 '-fluoro-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) -3, 6-diazabicyclo [3.1.1] heptan-6-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05480)
The title compound (GT-05480) was prepared according to the method of scheme 1 (white solid, 22mg, yield 29.72%). 1 H NMR(400MHz,DMSO)δ11.04(s,1H),7.95–7.58(m,3H),7.28(d,J＝23.8Hz,2H),7.14(dd,J＝18.2,9.8Hz,2H),5.13(d,J＝14.6Hz,1H),4.95–3.99(m,6H),3.94–3.39(m,4H),2.92(s,5H),2.63(d,J＝17.0Hz,1H),2.42(s,1H),2.06(d,J＝24.3Hz,3H),1.71(s,4H).LCMS(ESI)C 32 H 34 FN 4 O 4 + [M+H] + Calculated 557.26, measured 557.3.
Example 182: preparation of 2- (2, 6-dioxopiperidin-3-yl) -5- ((3- (4 '-fluoro-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) -3, 6-diazabicyclo [3.1.1] heptane-6-yl) methyl) isoindoline-1, 3-dione (GT-05481)
The title compound (GT-05481) was prepared according to the method of scheme 1 (white solid, 30mg, yield 31.59%). 1 H NMR(400MHz,DMSO)δ11.65–11.25(m,1H),11.14(s,1H),9.60(s,1H),8.37–7.12(m,7H),5.26–5.08(m,1H),4.57(d,J＝107.3Hz,3H),3.60(s,6H),3.17(s,2H),2.95–2.82(m,1H),2.61(d,J＝18.7Hz,2H),2.38(s,1H),2.13(t,J＝28.9Hz,3H),1.72(s,4H).LCMS(ESI)C 32 H 32 FN 4 O 5 + [M+H] + Calculated 571.24, found 571.3.
Example 183: preparation of 5- ((4- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-05497)
The title compound (GT-05497) (white solid, 40mg, yield 45.77%) was prepared according to the method of scheme 1. 1 H NMR(400MHz,DMSO-d6)δ11.15(s,1H),8.17(s,1H),8.02(dd,J＝27.5,7.6Hz,2H),7.94(d,J＝7.8Hz,1H),7.56–7.47(m,4H),7.39(d,J＝8.4Hz,2H),7.30(dd,J＝5.6,3.4Hz,1H),5.22–5.12(m,1H),4.61–4.08(m,4H),3.29(s,9H),2.59(s,1H),2.54(s,1H),2.07(dd,J＝9.2,3.6Hz,1H).LCMS(ESI)C 31 H 30 ClN 4 O 4 + [M+H] + Calculated 557.20, found 557.2.
Example 184: preparation of 3- (5- (4- ((4- (4-chlorophenyl) -6, 6-dimethyl-5, 6-dihydro-2H-pyran-3-yl) methyl) piperazine-1-carbonyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05673)
The title compound (GT-05673) (white solid, 15mg, 20.36% yield) was prepared according to the procedure of synthesis scheme 6 and example 76. 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),7.86–7.77(m,1H),7.69–7.57(m,2H),7.48(ddd,J＝17.4,6.2,2.9Hz,3H),7.23(d,J＝8.4Hz,1H),5.15(dt,J＝8.0,5.7Hz,1H),4.46(dt,J＝34.6,17.7Hz,4H),3.79(d,J＝125.2Hz,6H),3.23–3.07(m,2H),2.91(dd,J＝20.6,7.9Hz,4H),2.61(d,J＝16.5Hz,1H),2.44–2.36(m,1H),2.22(s,1H),2.03(dd,J＝16.2,9.3Hz,1H),1.47(d,J＝20.0Hz,3H),1.22(s,3H).LCMS(ESI)C 32 H 36 ClN 4 O 5 + [M+H] + Calculated 591.24, found 591.3.
Example 185: preparation of 5- (4- ((4- (4-chlorophenyl) -6, 6-dimethyl-5, 6-dihydro-2H-pyran-3-yl) methyl) piperazine-1-carbonyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-05674)
The title compound (GT-05674) (white solid, 22mg, yield 29.17%) was prepared according to the procedure of synthesis scheme 6 and example 76. 1 H NMR(400MHz,DMSO-d6)δ11.15(s,1H),10.11(s,1H),8.05–7.84(m,3H),7.49(d,J＝8.0Hz,2H),7.23(d,J＝8.0Hz,2H),5.19(dd,J＝12.8,5.4Hz,1H),4.34(d,J＝60.7Hz,2H),3.60(d,J＝40.9Hz,5H),3.33–3.17(m,4H),2.99–2.85(m,2H),2.58(dd,J＝23.8,11.5Hz,2H),2.20(s,2H),2.10–2.02(m,1H),1.24(d,J＝17.4Hz,6H).LCMS(ESI)C 32 H 34 ClN 4 O 6 + [M+H] + Calculated 605.22, measured 605.3.
Example 186: preparation of 3- (5- ((1- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperidin-4-yl) amino) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05782)
The title compound (GT-05782) was prepared according to the method of FIG. 4 (white solid, 20mg, yield 21.62%). 1 H NMR(400MHz,DMSO-d6)δ10.92(s,1H),9.99(d,J＝44.0Hz,1H),7.43(dd,J＝31.8,8.3Hz,3H),7.16(d,J＝8.4Hz,2H),6.67(d,J＝9.4Hz,2H),5.01(dd,J＝13.3,5.1Hz,1H),4.19(d,J＝35.0Hz,2H),3.52(d,J＝5.1Hz,4H),3.32(d,J＝11.6Hz,4H),2.89(td,J＝13.0,6.7Hz,1H),2.70(d,J＝11.9Hz,1H),2.62–2.54(m,1H),2.34(d,J＝7.7Hz,3H),2.05(s,5H),1.48(s,2H),0.97(s,6H).LCMS(ESI)C 33 H 40 ClN 4 O 3 + [M+H] + Calculated 575.28, measured 575.28.
Example 187: preparation of 3- (5- ((1- (4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) piperidin-4-yl) amino) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05783)
The title compound (GT-05783) was prepared according to the method of scheme 6 (white solid, 25mg, yield 28.17%). 1 H NMR(400MHz,DMSO-d6)δ10.91(s,1H),7.37(t,J＝8.5Hz,3H),7.26(dd,J＝16.5,8.2Hz,2H),6.64(d,J＝15.3Hz,2H),5.00(dd,J＝13.3,4.9Hz,1H),4.31–4.02(m,3H),3.50(s,4H),3.35–3.21(m,2H),3.07(s,1H),2.93–2.79(m,1H),2.57(d,J＝17.0Hz,2H),2.39–2.30(m,2H),2.09(d,J＝17.3Hz,1H),2.00–1.87(m,2H),1.71(d,J＝48.3Hz,2H),1.45(d,J＝6.1Hz,2H),1.20(s,1H),0.98(d,J＝11.4Hz,6H).LCMS(ESI)C 33 H 38 ClN 4 O 4 + [M+H] + Calculated 589.26, found 589.3.
Example 188: preparation of 3- (5- ((1- (4 '-chloro- [1,1' -biphenyl ] -2-carbonyl) piperidin-4-yl) amino) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05784)
Referring to FIG. 6The procedure produced the title compound (GT-05784) (white solid, 25mg, yield 26.10%). 1 H NMR(400MHz,DMSO-d6)δ10.91(s,1H),7.67–7.23(m,9H),6.66(d,J＝8.8Hz,2H),5.00(dd,J＝13.3,5.0Hz,1H),4.22(s,3H),3.56(s,2H),3.20(d,J＝12.7Hz,1H),3.01(t,J＝12.1Hz,1H),2.93–2.81(m,1H),2.77–2.53(m,2H),2.33(qd,J＝13.2,4.4Hz,1H),2.02–1.80(m,2H),1.61(dd,J＝47.3,12.0Hz,1H),1.39–1.13(m,1H),1.09–0.35(m,1H).LCMS(ESI)C 31 H 30 ClN 4 O 4 + [M+H] + Calculated 557.20, found 557.2.
Example 189: preparation of 3- (5- ((1- ((4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperidin-4-yl) amino) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05785)
The title compound (GT-05785) was prepared according to the method of FIG. 4 (white solid, 20mg, yield 20.79%). 1 H NMR(400MHz,DMSO-d6)δ10.92(s,1H),9.99(d,J＝36.0Hz,1H),7.39(d,J＝8.2Hz,1H),7.31–7.13(m,4H),6.68(d,J＝8.9Hz,2H),5.01(dd,J＝13.2,5.1Hz,1H),4.19(dd,J＝51.6,16.8Hz,2H),3.52(d,J＝4.7Hz,4H),3.32(d,J＝11.6Hz,4H),2.90(dd,J＝22.4,8.8Hz,1H),2.68(d,J＝12.0Hz,3H),2.34(d,J＝7.6Hz,2H),2.07–1.87(m,5H),1.48(t,J＝6.0Hz,2H),0.97(s,6H).LCMS(ESI)C 33 H 40 FN 4 O 3 + [M+H] + Calculated 559.31, measured 559.3.
Example 190: preparation of 3- (5- ((1- (4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) piperidin-4-yl) amino) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05786)
The title compound (GT-05786) was prepared according to the method of FIG. 6 (white solid, 25mg, yield 27.10%). 1 H NMR(400MHz,DMSO-d6)δ10.92(s,1H),7.36(d,J＝8.7Hz,1H),7.33–7.21(m,2H),7.14(t,J＝8.8Hz,2H),6.65(d,J＝18.4Hz,2H),5.00(dd,J＝13.3,5.0Hz,1H),4.34–4.09(m,3H),3.32(s,4H),3.07–2.74(m,2H),2.57(d,J＝14.1Hz,2H),2.41–2.31(m,2H),2.08(d,J＝17.7Hz,1H),1.92(dd,J＝14.8,10.2Hz,2H),1.82–1.57(m,2H),1.51–1.37(m,2H),1.19(s,1H),0.99(d,J＝12.1Hz,6H).LCMS(ESI)C 33 H 38 FN 4 O 4 + [M+H] + Calculated 573.29, measured 573.3.
Example 191: preparation of 3- (5- ((1- (4 '-chloro- [1,1' -biphenyl ] -2-carbonyl) piperidin-4-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05467)
The title compound (GT-05467) was prepared according to the method of FIG. 6 (white solid, 24mg, yield 36.84%). 1 H NMR(400MHz,DMSO)δ10.98(s,1H),7.61(d,J＝8.0Hz,1H),7.51–7.44(m,6H),7.35(d,J＝8.9Hz,2H),7.28(d,J＝7.9Hz,2H),5.09(dd,J＝13.1,4.9Hz,1H),4.52–4.29(m,3H),3.44(dd,J＝14.0,7.0Hz,2H),3.19(s,2H),3.06–2.86(m,2H),2.64–2.53(m,2H),2.38(d,J＝12.7Hz,2H),2.00(s,1H),1.73–1.47(m,2H),1.23–0.99(m,2H).LCMS(ESI)C 32 H 31 ClN 3 O 4 + [M+H] + Calculated 556.20, measured 556.3.
Example 192: preparation of 3- (5- ((1- (4 '-chloro- [1,1' -biphenyl ] -2-carbonyl) azetidin-3-ylidene) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05482)
The title compound (GT-05482) was prepared according to the method of FIG. 6 (white solid, 22mg, yield 32.55%). 1 H NMR(400MHz,DMSO)δ10.98(d,J＝4.5Hz,1H),7.66(dd,J＝15.8,7.9Hz,1H),7.56–7.43(m,7H),7.31(dd,J＝38.8,31.2Hz,2H),6.48(d,J＝37.5Hz,1H),5.10(s,1H),4.96–4.60(m,3H),4.36(dd,J＝34.3,17.3Hz,3H),2.99–2.84(m,1H),2.62(s,1H),2.43–2.33(m,1H),2.00(d,J＝5.7Hz,1H).LCMS(ESI)C 30 H 25 ClN 3 O 4 + [M+H] + Calculated 526.15, found 526.1.
Example 193: preparation of 3- (5- ((1- (4 '-chloro- [1,1' -biphenyl ] -2-carbonyl) -3-hydroxyazetidin-3-yl) (hydroxy) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05484)
The title compound (GT-05484) was prepared according to the method of FIG. 6 (white solid, 17mg, 26.12% yield). 1 H NMR(400MHz,DMSO)δ10.99(d,J＝5.7Hz,1H),7.63(dd,J＝11.9,7.9Hz,1H),7.56–7.40(m,10H),7.38–7.27(m,1H),5.89(d,J＝44.4Hz,2H),5.15–5.02(m,1H),4.54–4.38(m,2H),4.35–4.24(m,1H),4.12(d,J＝9.6Hz,1H),3.82(d,J＝9.4Hz,1H),3.47–3.38(m,1H),3.26(d,J＝9.1Hz,1H),2.91(d,J＝3.8Hz,1H),2.60(d,J＝16.0Hz,1H),2.39(s,1H),1.99(d,J＝7.4Hz,1H).LCMS(ESI)C 30 H 27 ClN 3 O 6 + [M+H] + Calculated 560.16, measured 560.2.
Example 194: preparation of 3- (5- ((1- ((4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) azetidin-3-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05493)
The title compound (GT-05493) was prepared according to the method of FIG. 4 (white solid, 18mg, yield 21.30%). 1 H NMR(400MHz,DMSO-d6)δ11.10(s,1H),10.99(s,1H),10.80(s,1H),7.65(d,J＝7.9Hz,1H),7.47–7.31(m,2H),7.29–7.17(m,4H),5.10(dd,J＝13.1,4.0Hz,1H),4.36(dd,J＝51.3,17.3Hz,2H),4.03(s,1H),3.92–3.56(m,4H),3.37(s,2H),3.20(d,J＝8.0Hz,1H),2.90(ddd,J＝30.8,22.4,10.9Hz,3H),2.60(d,J＝16.4Hz,1H),2.40(dd,J＝13.0,4.0Hz,1H),2.06(t,J＝41.0Hz,5H),1.42(d,J＝4.9Hz,1H),1.09–0.91(m,6H).LCMS(ESI)C 32 H 37 FN 3 O 3 + [M+H] + Calculated 530.28, measured 530.3.
Example 195: preparation of 3- (5- ((1- ((4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) azetidin-3-ylidene) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05483)
The title compound (GT-05483) was prepared according to the method of FIG. 4 (white solid, 5mg, yield 5.5%). 1 H NMR(400MHz,DMSO-d6)δ10.99(s,1H),10.87(s,1H),7.69(t,J＝11.5Hz,1H),7.37–7.13(m,6H),6.54(s,1H),5.24–5.02(m,2H),4.99–4.80(m,2H),4.63–4.30(m,3H),3.82(s,1H),3.20–2.82(m,3H),2.61(d,J＝15.9Hz,1H),2.40(dd,J＝12.9,4.3Hz,1H),2.22(s,2H),2.02(dd,J＝15.2,10.0Hz,3H),1.46(t,J＝6.3Hz,2H),1.07–0.92(m,6H).LCMS(ESI)C 32 H 35 FN 3 O 3 + [M+H] + Calculated 528.27, measured 528.3.
Example 196: preparation of 3- (5- (3- ((4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -3, 8-diazabicyclo [3.2.1] octane-8-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05498)
The title compound (GT-05498) was prepared according to the method of FIG. 4 (white solid, 32mg, yield 39.17%). 1 H NMR(400MHz,DMSO-d6)δ10.96(s,1H),10.37(s,1H),7.55(dd,J＝15.9,8.4Hz,1H),7.19–6.94(m,6H),5.10(dd,J＝13.1,5.0Hz,1H),4.50(s,2H),4.31(dd,J＝35.5,16.9Hz,2H),3.38(s,4H),3.07–2.78(m,5H),2.61(d,J＝17.3Hz,1H),2.46–2.39(m,1H),2.28(d,J＝7.7Hz,2H),2.13(s,2H),1.99(d,J＝35.5Hz,5H),1.34(s,2H),0.86(t,J＝16.5Hz,6H).LCMS(ESI)C 34 H 40 FN 4 O 3 + [M+H] + Calculated 571.31, found 571.3.
Example 197: preparation of 3- (5- ((1- ((4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -3-hydroxyazetidin-3-yl) (hydroxy) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05499)
The title compound (GT-05499) was prepared according to the method of FIG. 4 (white solid, 18mg, yield 28.78%). 1 H NMR(400MHz,DMSO-d6)δ10.99(s,1H),10.39(s,1H),7.74–7.55(m,2H),7.39–7.18(m,5H),6.31–6.13(m,2H),5.11(d,J＝13.3Hz,1H),4.41(ddd,J＝38.1,15.8,8.6Hz,3H),3.97–3.59(m,3H),3.54–3.35(m,4H),2.92(t,J＝14.9Hz,1H),2.61(d,J＝15.8Hz,1H),2.41(dd,J＝15.4,11.0Hz,1H),2.22–2.01(m,4H),1.43(d,J＝6.2Hz,2H),1.00–0.90(m,6H).LCMS(ESI)C 32 H 37 FN 3 O 5 + [M+H] + Calculated 562.27, measured 562.3.
Example 198: preparation of 3- (5- (8- ((4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05500)
The title compound (GT-05500) was prepared according to the method of FIG. 4 (white solid, 20mg, yield 24.84%). 1 H NMR(400MHz,DMSO-d6)δ10.94(s,1H),10.42(s,1H),7.55(d,J＝8.4Hz,1H),7.31–7.22(m,4H),7.00(d,J＝11.5Hz,2H),5.05(dd,J＝13.2,5.0Hz,1H),4.27(dd,J＝50.0,17.1Hz,3H),3.90(s,2H),3.74(d,J＝12.7Hz,2H),3.57(d,J＝12.3Hz,4H),2.60(s,1H),2.41(d,J＝16.4Hz,2H),2.13(s,2H),2.01–1.90(m,2H),1.74(d,J＝8.3Hz,2H),1.51(t,J＝6.0Hz,2H),1.33–1.25(m,2H),0.99(s,6H).LCMS(ESI)C 34 H 40 FN 4 O 3 + [M+H] + Calculated 571.31, found 571.3.
Example 199: preparation of 3- (5- ((1- (4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) piperidin-4-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05487)
The title compound (GT-05487) was prepared according to the method of FIG. 6 (white solid, 8mg, yield 8.69%). 1 H NMR(400MHz,DMSO-d6)δ10.98(s,1H),7.62(d,J＝7.7Hz,1H),7.38–7.27(m,2H),7.26–7.11(m,4H),5.10(dd,J＝13.1,4.9Hz,1H),4.56–4.16(m,3H),3.47(d,J＝12.8Hz,2H),3.33–3.22(m,2H),2.91(t,J＝12.9Hz,1H),2.63(dd,J＝39.4,27.3Hz,2H),2.44–2.31(m,4H),2.19–1.89(m,4H),1.66–1.33(m,5H),0.97(d,J＝9.3Hz,6H).LCMS(ESI)C 34 H 39 FN 3 O 4 + [M+H] + Calculated 572.29, measured 572.3.
Example 200: preparation of 3- (5- ((1- (4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) azetidin-3-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05488)
The title compound (GT-05488) was prepared according to the method of FIG. 6 (white solid, 18mg, 20.56% yield). 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),7.62(d,J＝7.8Hz,1H),7.32(dd,J＝8.5,5.7Hz,2H),7.27–7.20(m,3H),7.15(d,J＝7.8Hz,1H),5.10(dd,J＝13.2,4.9Hz,1H),4.35(dd,J＝55.0,17.0Hz,2H),3.66(dt,J＝15.5,8.1Hz,2H),3.26(dd,J＝9.7,4.1Hz,1H),3.01(d,J＝5.8Hz,1H),2.89(dd,J＝13.0,4.6Hz,1H),2.57(dd,J＝21.4,12.3Hz,3H),2.41(ddd,J＝17.9,12.0,6.1Hz,2H),2.32–2.12(m,3H),2.01(dd,J＝20.5,12.1Hz,2H),1.39(t,J＝6.4Hz,2H),0.95(d,J＝1.4Hz,6H).LCMS(ESI)C 32 H 35 FN 3 O 4 + [M+H] + Calculated 544.26, measured 544.3.
Example 201: preparation of 3- (5- ((1- (4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) azetidin-3-ylmethylene) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05489)
The title compound (GT-05489) was prepared according to the method of FIG. 6 (white solid, 13mg, 15.00% yield). 1 H NMR(400MHz,DMSO-d6)δ10.99(d,J＝6.1Hz,1H),7.66(dd,J＝11.4,7.9Hz,1H),7.36–7.29(m,2H),7.28–7.08(m,4H),6.40(d,J＝16.6Hz,1H),5.18–5.04(m,1H),4.72–4.43(m,2H),4.41–4.23(m,3H),2.97–2.86(m,1H),2.60(d,J＝16.4Hz,1H),2.39(dd,J＝28.3,16.2Hz,3H),2.18–1.97(m,3H),1.44(dd,J＝12.3,6.1Hz,2H),1.24–1.05(m,1H),1.05–0.93(m,6H).LCMS(ESI)C 32 H 33 FN 3 O 4 + [M+H] + Calculated 542.25, measured 542.3.
Example 202: preparation of 3- (5- ((1- (4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) -3-hydroxyazetidin-3-yl) (hydroxy) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05490)
The title compound (GT-05490) was prepared according to the method of scheme 6 (white solid, 8mg, yield 8.60%). 1 H NMR(400MHz,DMSO-d6)δ10.99(s,1H),7.62(dd,J＝7.8,2.1Hz,1H),7.48–7.33(m,2H),7.29(ddd,J＝17.8,8.5,4.3Hz,2H),7.21–7.10(m,2H),5.66(s,2H),5.11(dd,J＝13.3,5.0Hz,1H),4.36(ddd,J＝19.7,16.2,8.4Hz,3H),3.92–3.77(m,1H),3.66(d,J＝9.0Hz,1H),3.30–3.08(m,4H),2.97–2.86(m,1H),2.60(d,J＝17.1Hz,1H),2.40(dd,J＝17.9,8.4Hz,1H),2.08(dd,J＝60.3,22.8Hz,5H),1.39(d,J＝5.6Hz,2H),0.99–0.93(m,6H).LCMS(ESI)C 32 H 35 FN 3 O 6 + [M+H] + Calculated 576.25, measured 576.3.
Example 203: preparation of 3- (5- (8- (4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) -3, 8-diazabicyclo [3.2.1] octane-3-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05491)
The title compound (GT-05491) was prepared according to the method of FIG. 6 (white solid, 14mg, 14.86% yield). 1 H NMR(400MHz,DMSO-d6)δ10.94(s,1H),7.48(d,J＝8.5Hz,1H),7.41–7.29(m,2H),7.14(s,2H),6.90(s,2H),5.03(dd,J＝13.3,5.0Hz,1H),4.54(s,1H),4.23(dd,J＝50.5,16.9Hz,2H),3.89(s,1H),3.59(d,J＝10.4Hz,1H),3.36(s,4H),2.98–2.69(m,2H),2.58(d,J＝16.9Hz,1H),2.35(ddd,J＝26.4,13.2,4.5Hz,4H),2.04–1.87(m,2H),1.51(d,J＝41.9Hz,4H),1.01(d,J＝3.8Hz,6H).LCMS(ESI)C 34 H 38 FN 4 O 4 + [M+H] + Calculated 585.29, measured 585.3.
Example 204: preparation of 3- (5- (3- (4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) -3, 8-diazabicyclo [3.2.1] octane-8-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05492)
The title compound (GT-05492) was prepared according to the method of FIG. 6 (white solid, 18mg, 19.11% yield). 1 H NMR(400MHz,DMSO-d6)δ10.81(s,1H),7.38–7.25(m,2H),7.08(t,J＝8.8Hz,1H),6.99(d,J＝5.6Hz,1H),6.92–6.77(m,2H),6.71(s,1H),4.97–4.87(m,1H),4.13(dt,J＝48.5,13.4Hz,4H),3.65(d,J＝13.0Hz,1H),3.26(s,2H),3.09(dd,J＝59.1,12.6Hz,2H),2.75(d,J＝12.7Hz,1H),2.45(d,J＝17.1Hz,1H),2.35–2.17(m,3H),2.03(s,1H),1.93–1.75(m,3H),1.37(d,J＝86.6Hz,4H),0.86(dd,J＝18.9,6.3Hz,6H).LCMS(ESI)C 34 H 38 FN 4 O 4 + [M+H] + Calculated 585.29, measured 585.3.
Example 205: preparation of 3- (5- ((6- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05685)
The title compound (GT-05685) was prepared according to the method of scheme 1 (white solid, 8mg, yield 11.27%). 1 H NMR(400MHz,DMSO-d6)δ11.01(s,2H),7.79(s,1H),7.68(s,1H),7.59(s,1H),7.43(d,J＝8.3Hz,2H),7.15(d,J＝8.2Hz,2H),5.13(dd,J＝13.2,4.9Hz,1H),4.53–4.11(m,6H),3.88(s,4H),3.42(s,2H),2.91(d,J＝13.7Hz,3H),2.61(d,J＝17.2Hz,1H),2.41(d,J＝8.2Hz,1H),2.15(s,2H),2.01(s,3H),1.42(d,J＝5.7Hz,2H),0.95(d,J＝10.0Hz,6H).LCMS(ESI)C 34 H 40 ClN 4 O 3 + [M+H] + Calculated 587.28, measured 587.3.
Example 206: preparation of 5- ((6- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -2, 6-diazaspiro [3.3] heptane-2-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-05675)
The title compound (GT-05675) was prepared according to the method of scheme 1 (white solid, 8mg, yield 11.17%). 1 H NMR(400MHz,DMSO-d6)δ11.14(s,1H),7.97(d,J＝34.8Hz,3H),7.43(d,J＝8.4Hz,2H),7.32–7.13(m,2H),5.17(dd,J＝12.7,5.2Hz,1H),4.49(s,1H),4.21(s,4H),3.66(d,J＝43.9Hz,6H),3.24–3.01(m,2H),2.90(t,J＝12.8Hz,1H),2.61(d,J＝17.4Hz,1H),2.16–2.00(m,4H),1.42(d,J＝5.9Hz,2H),1.26(dt,J＝7.4,5.1Hz,1H),0.96(d,J＝10.3Hz,6H).LCMS(ESI)C 34 H 38 ClN 4 O 4 + [M+H] + Calculated 601.26, found 601.3.
Example 207: preparation of 5- (6- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -2, 6-diazaspiro [3.3] heptane-2-carbonyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-05676)
The title compound (GT-05676) (white solid, 9mg, 12.10% yield) was prepared according to the procedure of synthesis scheme 6 and example 76. 1 H NMR(400MHz,DMSO-d6)δ11.15(s,1H),10.37(d,J＝84.9Hz,1H),8.15–7.94(m,3H),7.43(d,J＝22.4Hz,2H),7.15(s,2H),5.19(dd,J＝12.7,5.4Hz,1H),4.22(d,J＝17.6Hz,3H),3.93(d,J＝55.3Hz,3H),3.62(s,1H),3.36(s,2H),3.31(s,3H),2.91(dd,J＝22.3,9.0Hz,1H),2.64–2.55(m,1H),2.13–2.00(m,4H),1.42(s,2H),0.94(s,6H).LCMS(ESI)C 34 H 36 ClN 4 O 5 + [M+H] + Calculated 615.24, measured 615.3.
Example 208: preparation of 3- (5- ((7- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05677)
The title compound (GT-05677) was prepared according to the method of scheme 1 (white solid, 10mg, 14.59% yield). 1 H NMR(400MHz,DMSO-d6)δ11.66(s,1H),11.01(s,1H),9.73(s,1H),7.86–7.68(m,3H),7.43(dd,J＝10.3,8.5Hz,2H),7.13(dd,J＝10.8,8.4Hz,2H),5.13(dd,J＝13.4,4.7Hz,1H),4.56–4.25(m,4H),4.00–3.61(m,4H),3.48(s,2H),3.22(dd,J＝35.0,20.6Hz,4H),2.92(dd,J＝21.6,8.9Hz,1H),2.61(d,J＝16.7Hz,2H),2.43(dd,J＝12.9,4.3Hz,1H),2.30(s,2H),2.06(d,J＝39.1Hz,6H),1.45(t,J＝6.1Hz,2H),0.96(d,J＝10.5Hz,6H).LCMS(ESI)C 36 H 44 ClN 4 O 3 + [M+H] + Calculated 615.31, measured 615.3.
Example 209: preparation of 5- ((7- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-05678)
The title compound (GT-05678) (white solid, 20mg, yield 28.17%) was prepared according to the method of FIG. 1. 1 H NMR(400MHz,DMSO-d6)δ11.83(s,1H),11.15(s,1H),9.74(s,1H),8.18(s,1H),8.04(dd,J＝26.5,7.7Hz,2H),7.42(t,J＝7.5Hz,2H),7.11(d,J＝8.3Hz,2H),5.18(dd,J＝12.8,5.5Hz,1H),4.69–4.44(m,2H),3.87(dd,J＝64.6,29.5Hz,4H),3.48(s,3H),3.20(s,3H),2.89(dd,J＝16.7,4.9Hz,1H),2.59(dd,J＝23.5,11.3Hz,3H),2.31(s,3H),2.15–2.01(m,6H),1.45(t,J＝6.0Hz,2H),0.95(s,6H).LCMS(ESI)C 36 H 42 ClN 4 O 4 + [M+H] + Calculated 629.29, measured 629.3.
Example 210: preparation of 5- (7- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -2, 7-diazaspiro [3.5] nonane-2-carbonyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-05679)
The title compound (GT-05679) (white solid, 12mg, 16.74% yield) was prepared according to the procedure of synthesis scheme 6 and example 76. 1 H NMR(400MHz,DMSO-d6)δ11.15(s,1H),8.95(s,1H),8.17–7.98(m,3H),7.43(dd,J＝25.3,8.2Hz,2H),7.12(dd,J＝24.2,8.3Hz,2H),5.18(dd,J＝12.8,5.4Hz,1H),4.13–3.75(m,4H),3.55(s,2H),3.37(d,J＝2.6Hz,2H),3.31(dd,J＝5.6,2.5Hz,2H),3.18(d,J＝10.8Hz,2H),3.01–2.85(m,1H),2.62(d,J＝18.7Hz,2H),2.24(s,2H),2.00(d,J＝16.9Hz,5H),1.47(s,2H),0.95(s,6H).LCMS(ESI)C 36 H 40 ClN 4 O 5 + [M+H] + Calculated 643.27, measured 643.3.
Example 211: preparation of 3- (5- ((5- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) methyl) -1-oxo-isoindolin-2-yl) piperidine-2, 6-dione (GT-05653)
The title compound (GT-05653) was prepared according to the method of scheme 1 (white solid, 25mg, yield 28.69%). 1 H NMR(400MHz,DMSO-d6)δ11.52(d,J＝60.0Hz,1H),11.01(s,1H),10.76(d,J＝95.5Hz,1H),7.79(d,J＝8.2Hz,3H),7.48–7.34(m,2H),7.15(dd,J＝8.1,5.8Hz,2H),5.14(dd,J＝13.2,5.1Hz,1H),4.43(d,J＝33.9Hz,4H),3.81(d,J＝8.9Hz,1H),3.55(d,J＝59.1Hz,6H),3.27(s,3H),3.16–3.03(m,2H),3.00–2.84(m,2H),2.61(d,J＝16.9Hz,1H),2.49–2.43(m,1H),2.31(s,1H),2.02(s,3H),1.52–1.38(m,2H),0.96(d,J＝8.8Hz,6H).LCMS(ESI)C 35 H 42 ClN 4 O 3 + [M+H] + Calculated 601.29, found 601.3.
Example 212: preparation of 5- ((5- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-05654)
The title compound (GT-05654) was prepared according to the method of scheme 1 (white solid, 50mg, yield 56.28%). 1 H NMR(400MHz,DMSO-d6)δ11.30(s,1H),11.15(s,1H),10.53(d,J＝46.7Hz,1H),8.10(ddd,J＝27.2,24.3,7.7Hz,3H),7.41(dd,J＝18.2,8.1Hz,2H),7.23–7.05(m,2H),5.18(dd,J＝12.8,5.3Hz,1H),4.58(d,J＝39.6Hz,2H),3.86–3.48(m,6H),3.37(s,3H),3.15(d,J＝70.7Hz,4H),2.92(dd,J＝22.3,8.7Hz,2H),2.61(d,J＝17.8Hz,1H),2.48–2.43(m,1H),2.30(d,J＝18.5Hz,1H),2.11–2.00(m,3H),1.45(s,2H),0.96(d,J＝8.4Hz,6H).LCMS(ESI)C 35 H 40 ClN 4 O 4 + [M+H] + Calculated 615.27, measured 615.3.
Example 213: preparation of 5- (5- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) octahydropyrrolo [3,4-c ] pyrrole-2-carbonyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-05655)
The title compound (GT-05655) (white solid, 35mg, yield 47.97%) was prepared according to the procedure of synthesis scheme 6 and example 76. 1 H NMR(400MHz,DMSO-d6)δ11.15(s,1H),10.47(d,J＝72.6Hz,1H),7.95(ddd,J＝39.3,19.6,7.6Hz,3H),7.45(t,J＝8.7Hz,2H),7.16(dd,J＝8.3,3.5Hz,2H),5.20(dd,J＝12.8,5.7Hz,1H),3.79–3.49(m,7H),3.24(s,2H),2.94(dd,J＝37.3,22.8Hz,3H),2.74–2.53(m,3H),2.29(s,2H),2.14–1.97(m,3H),1.46(d,J＝5.9Hz,2H),0.96(s,6H).LCMS(ESI)C 35 H 38 ClN 4 O 5 + [M+H] + Calculated 629.25, measured 629.3.
Example 214: preparation of 3- (5- ((4- (4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) -1, 4-diazepan-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05680)
The title compound (GT-05680) was prepared according to the method of scheme 1 (white solid, 35mg, yield 50.15%). 1 H NMR(400MHz,DMSO-d6)δ11.38(d,J＝71.0Hz,1H),11.01(s,1H),7.91–7.77(m,2H),7.74(d,J＝7.0Hz,1H),7.53(s,1H),7.36(d,J＝8.4Hz,2H),7.22(d,J＝9.1Hz,1H),5.14(dd,J＝13.2,5.0Hz,1H),4.58–4.34(m,3H),4.08(s,2H),3.80–3.42(m,2H),3.19(s,4H),3.09–2.92(m,2H),2.61(d,J＝16.5Hz,1H),2.39(dd,J＝30.8,14.5Hz,3H),2.19(s,2H),2.05–1.78(m,3H),1.46(d,J＝5.7Hz,2H),0.98(t,J＝10.5Hz,6H).LCMS(ESI)C 34 H 40 ClN 4 O 4 + [M+H] + Calculated 603.27, measured 603.3.
Example 215: preparation of 3- (5- ((7- (4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) -2, 7-diazaspiro [3.5] nonan-2-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05656)
The title compound (GT-05656) was prepared according to the method of scheme 1 (white solid, 23mg, yield 27.17%). 1 H NMR(400MHz,DMSO-d6)δ11.69(d,J＝83.0Hz,1H),11.01(s,1H),7.75(ddd,J＝28.8,14.8,10.5Hz,3H),7.35(d,J＝8.4Hz,2H),7.24(d,J＝6.8Hz,2H),5.13(dd,J＝13.2,4.9Hz,1H),4.41(dd,J＝53.3,17.4Hz,4H),3.84–3.58(m,6H),3.34–3.07(m,4H),3.02–2.86(m,2H),2.61(d,J＝17.3Hz,1H),2.38(dd,J＝18.5,10.6Hz,2H),2.11–1.97(m,2H),1.81(dd,J＝68.4,17.3Hz,3H),1.38(d,J＝55.4Hz,3H),0.98(d,J＝14.5Hz,6H).LCMS(ESI)C 36 H 42 ClN 4 O 4 + [M+H] + Calculated 629.29, measured 629.3.
Example 216: preparation of 3- (5- (7- (4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) -2, 7-diazaspiro [3.5] nonane-2-carbonyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05657)
The title compound (GT-05657) (white solid, 6mg, yield 8.72%) was prepared according to the procedure of synthesis scheme 6 and example 76. 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),7.82(s,1H),7.74(dd,J＝23.1,7.8Hz,2H),7.36(dd,J＝23.6,8.0Hz,2H),7.24(t,J＝10.5Hz,2H),5.12(dd,J＝13.3,5.1Hz,1H),4.42(dd,J＝50.8,17.6Hz,2H),4.01–3.60(m,3H),3.48(dd,J＝23.6,8.5Hz,4H),3.21(dd,J＝21.5,16.5Hz,2H),3.05(s,1H),2.90(dd,J＝16.9,8.5Hz,1H),2.61(d,J＝16.1Hz,1H),2.44–2.31(m,3H),2.14–1.87(m,3H),1.52(d,J＝64.3Hz,4H),0.97(d,J＝13.1Hz,6H).LCMS(ESI)C 36 H 40 ClN 4 O 5 + [M+H] + Calculated 643.27, measured 643.27.
Example 217: preparation of 3- (5- ((6- (4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) -2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05681)
The title compound (GT-05681) was prepared according to the method of scheme 1 (white solid, 11mg, yield 15.17%). 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),10.51(s,1H),7.79(d,J＝8.1Hz,1H),7.62(s,1H),7.53(s,1H),7.40(t,J＝8.8Hz,2H),7.25(dd,J＝14.5,8.5Hz,2H),5.13(dd,J＝13.4,5.0Hz,1H),4.42(dd,J＝50.6,17.7Hz,3H),4.00–3.49(m,8H),3.26(dd,J＝24.4,8.3Hz,2H),2.97–2.87(m,1H),2.61(d,J＝16.5Hz,1H),2.42(dd,J＝13.0,4.6Hz,1H),2.23(s,2H),2.12(s,1H),2.06–1.97(m,1H),1.40(d,J＝6.2Hz,2H),0.96(d,J＝7.6Hz,6H).LCMS(ESI)C 34 H 38 ClN 4 O 4 + [M+H] + Calculated 601.26, found 601.3.
Example 218: preparation of 3- (5- (6- (4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) -2, 6-diazaspiro [3.3] heptane-2-carbonyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05682)
The title compound (GT-05682) (white solid, 6mg, 16.82% yield) was prepared according to the procedure of synthesis scheme 6 and example 76. 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),7.77(d,J＝7.4Hz,2H),7.65(d,J＝8.4Hz,1H),7.40(d,J＝8.5Hz,2H),7.25(d,J＝8.5Hz,2H),5.13(dd,J＝13.3,5.0Hz,1H),4.43(d,J＝31.0Hz,2H),4.20(d,J＝9.0Hz,1H),4.00(dd,J＝16.8,10.1Hz,2H),3.79(d,J＝10.5Hz,3H),3.65(d,J＝16.6Hz,2H),3.01–2.86(m,1H),2.61(d,J＝16.8Hz,1H),2.44–2.32(m,1H),2.24(s,2H),2.12(s,2H),2.06–1.97(m,1H),1.40(t,J＝6.4Hz,2H),0.97(s,6H).LCMS(ESI)C 34 H 36 ClN 4 O 5 + [M+H] + Calculated 615.24, measured 615.3.
Example 219: preparation of 3- (5- ((5- (4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05658)
The title compound (GT-05658) was prepared according to the method of scheme 1 (white solid, 25mg, yield 36.17%). 1 H NMR(400MHz,DMSO-d6)δ11.47(d,J＝58.5Hz,1H),11.01(s,1H),7.82–7.68(m,3H),7.46–7.23(m,4H),5.14(dd,J＝13.2,4.9Hz,1H),4.59–4.27(m,4H),3.58(s,2H),3.19(dd,J＝40.2,26.4Hz,4H),2.97–2.73(m,4H),2.61(d,J＝16.7Hz,1H),2.43(dd,J＝13.0,4.1Hz,1H),2.34–2.00(m,6H),1.43(t,J＝6.0Hz,2H),0.99(s,6H).LCMS(ESI)C 35 H 40 ClN 4 O 4 + [M+H] + Calculated value 615.27, found 615.3.
Example 220: preparation of 3- (5- (5- (4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) octahydropyrrolo [3,4-c ] pyrrole-2-carbonyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05659)
The title compound (GT-05659) (white solid, 25mg, yield 35.17%) was prepared according to the procedure of synthesis scheme 6 and example 76. 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),7.79(t,J＝8.5Hz,1H),7.64(s,1H),7.51(s,1H),7.38(dd,J＝11.5,5.6Hz,2H),7.27(dd,J＝15.0,8.3Hz,2H),5.14(d,J＝13.1Hz,1H),4.55–4.34(m,2H),3.73–3.43(m,3H),3.32–2.89(m,5H),2.79–2.58(m,4H),2.42(d,J＝13.0Hz,1H),2.16(d,J＝96.6Hz,5H),1.50–1.34(m,2H),0.98(dd,J＝17.6,2.4Hz,6H).LCMS(ESI)C 35 H 38 ClN 4 O 5 + [M+H] + Calculated 629.25, measured 629.3.
Example 221: preparation of 3- (5- ((6- (4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05660)
The title compound (GT-05660) was prepared according to the procedure for synthesis scheme 1 (white solid, 35mg, yield 50.31%). 1 H NMR(400MHz,DMSO-d6)δ11.92(s,1H),11.01(s,1H),7.92(s,1H),7.81(s,2H),7.46(d,J＝8.1Hz,2H),7.27(d,J＝8.5Hz,2H),5.15(dd,J＝13.3,5.0Hz,1H),4.57–4.33(m,2H),4.30–4.10(m,2H),3.84(s,1H),3.51(s,4H),2.99–2.83(m,1H),2.63(t,J＝16.3Hz,2H),2.45(dd,J＝13.2,4.4Hz,1H),2.21(d,J＝19.1Hz,3H),2.07–1.95(m,2H),1.85(s,1H),1.65(d,J＝6.8Hz,1H),1.36(d,J＝6.1Hz,2H),0.94(s,6H).LCMS(ESI)C 34 H 38 ClN 4 O 4 + [M+H] + Calculated 601.26, found 601.3.
Example 222: preparation of 3- (5- (6- (4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) -3, 6-diazabicyclo [3.1.1] heptane-3-carbonyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05661)
Preparation of the target Compound (GT-0566) by the method of Synthesis scheme 6 and example 761) (white solid, 38mg, yield 53.21%). 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),7.80(dd,J＝10.2,4.9Hz,1H),7.54(d,J＝5.1Hz,1H),7.41(dd,J＝15.1,6.6Hz,3H),7.28(dd,J＝21.4,8.4Hz,2H),5.14(dd,J＝13.0,5.0Hz,1H),4.45(ddd,J＝17.6,13.6,7.7Hz,2H),3.97(d,J＝32.4Hz,1H),3.65(dt,J＝18.5,12.0Hz,2H),3.45(d,J＝13.1Hz,1H),3.30(s,2H),2.93(dd,J＝19.4,10.3Hz,1H),2.61(d,J＝16.5Hz,1H),2.43(td,J＝13.5,4.3Hz,2H),2.21(dd,J＝49.1,17.6Hz,2H),2.03(d,J＝17.3Hz,2H),1.83(d,J＝8.8Hz,1H),1.47–1.32(m,3H),1.01–0.82(m,6H).LCMS(ESI)C 34 H 36 ClN 4 O 5 + [M+H] + Calculated 615.24, measured 615.3.
Example 223: preparation of 3- (5- ((5- (4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) -2, 5-diazabicyclo [2.2.2] octane-2-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05662)
The title compound (GT-05662) was prepared according to the method of scheme 1 (white solid, 35mg, yield 51.32%). 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),8.01–7.57(m,3H),7.52–7.35(m,2H),7.34–7.13(m,2H),5.14(dd,J＝13.1,4.7Hz,1H),4.44(dd,J＝38.0,13.9Hz,3H),4.03(d,J＝50.0Hz,1H),3.80–3.38(m,5H),3.33–2.77(m,4H),2.61(d,J＝17.2Hz,1H),2.48–2.19(m,4H),2.02(t,J＝46.2Hz,3H),1.76(s,1H),1.44(s,2H),1.09–0.90(m,6H).LCMS(ESI)C 35 H 40 ClN 4 O 4 + [M+H] + Calculated 615.27, measured 615.3.
Example 224: preparation of 3- (5- (5- (4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) -2, 5-diazabicyclo [2.2.2] octane-2-carbonyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05663)
The title compound (GT-05663) (white solid, 30mg, yield 42.45%) was prepared according to the procedure of synthesis scheme 6 and example 76. 1 H NMR(400MHz,DMSO-d6)δ11.01(d,J＝4.4Hz,1H),7.83–7.72(m,1H),7.67–7.13(m,6H),5.13(dd,J＝12.5,5.6Hz,1H),4.71–4.18(m,3H),3.95–3.36(m,6H),3.23(dd,J＝28.1,12.4Hz,2H),2.94(dt,J＝17.2,14.3Hz,2H),2.41(dd,J＝26.1,13.1Hz,3H),2.06(t,J＝29.0Hz,2H),1.92–1.68(m,3H),1.42(s,2H),0.97(t,J＝15.8Hz,6H).LCMS(ESI)C 35 H 38 ClN 4 O 5 + [M+H] + Calculated 629.25, measured 629.3.
Example 225: preparation of 3- (5- ((5- (4 '-chloro- [1,1' -biphenyl ] -2-carbonyl) -2, 5-diazabicyclo [2.2.1] heptane-2-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05776)
The title compound (GT-05776) was prepared according to the procedure for synthesis scheme 1 (white solid, 25mg, 34.32% yield). 1 H NMR(400MHz,DMSO-d6)δ11.56(s,1H),11.01(s,1H),10.91(s,1H),7.84(ddd,J＝27.1,20.4,19.8Hz,3H),7.59–7.39(m,8H),5.14(dd,J＝13.2,5.1Hz,1H),4.42(dd,J＝50.3,17.8Hz,4H),3.88(dd,J＝26.8,12.8Hz,2H),3.48(d,J＝5.5Hz,2H),3.25(d,J＝11.1Hz,3H),3.12–2.87(m,2H),2.61(d,J＝17.2Hz,1H),2.42(dt,J＝12.7,6.6Hz,1H),2.07–1.94(m,1H).LCMS(ESI)C 32 H 30 ClN 4 O 4 + [M+H] + Calculated 569.20, measured 569.2.
Example 226: preparation of 3- (5- ((4- ((3- (4-chlorophenyl) pyridin-2-yl) methyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05778)
The title compound (GT-05778) (white solid, 30mg, yield 39.17%) was prepared according to the method of scheme 1. 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),8.72(dd,J＝5.0,1.5Hz,1H),7.96(dd,J＝7.8,1.3Hz,1H),7.85(s,1H),7.81(d,J＝7.8Hz,1H),7.74(d,J＝7.7Hz,1H),7.66(dd,J＝7.8,5.0Hz,1H),7.60(d,J＝8.5Hz,2H),7.51(d,J＝8.5Hz,2H),5.14(dd,J＝13.3,5.1Hz,1H),4.58–4.30(m,6H),3.36–3.25(m,8H),2.96–2.89(m,1H),2.61(d,J＝16.9Hz,1H),2.47–2.36(m,1H),2.06–1.96(m,1H).LCMS(ESI)C 30 H 31 ClN 5 O 3 + [M+H] + Calculated 544.21, measured 544.3.
Example 227: preparation of 3- (5- ((4- (2- (furan-2-yl) benzyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05779)
Square referring to synthesis scheme 1The title compound (GT-05779) was prepared as a white solid (31 mg, 37.17% yield). 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),7.94–7.67(m,6H),7.57–7.35(m,2H),6.93(s,1H),6.66(dd,J＝3.2,1.8Hz,1H),5.13(dd,J＝13.3,5.1Hz,1H),4.55–4.28(m,5H),3.39–3.03(m,9H),2.92(s,1H),2.61(d,J＝17.0Hz,1H),2.42(s,1H),2.00(s,1H).LCMS(ESI)C 29 H 31 N 4 O 4 + [M+H] + Calculated 499.23, found 499.3.
Example 228: preparation of 3- (5- ((4- (2- (1-methyl-1H-pyrrol-2-yl) benzyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05683)
The title compound (GT-05683) was prepared according to the method of scheme 1 (white solid, 30mg, yield 37.17%). 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),7.94(s,1H),7.88–7.69(m,3H),7.48(dd,J＝5.5,3.5Hz,2H),7.38–7.29(m,1H),6.88(s,1H),6.10(dd,J＝8.8,6.0Hz,2H),5.13(dd,J＝13.3,5.1Hz,1H),4.51–4.32(m,4H),4.17(s,2H),3.33(d,J＝37.7Hz,10H),2.98–2.84(m,2H),2.61(d,J＝16.8Hz,1H),2.43(dt,J＝13.3,8.8Hz,1H),2.07–1.95(m,1H).LCMS(ESI)C 30 H 34 N 5 O 3 + [M+H] + Calculated 512.27, measured 512.3.
Example 229: preparation of 3- (1-oxo-5- ((4- (2- (thiazol-5-yl) benzyl) piperazin-1-yl) methyl) isoindolin-2-yl) piperidine-2, 6-dione (GT-05684)
The title compound (GT-05684) was prepared according to the method of scheme 1 (white solid, 14mg, 17.32% yield). 1 H NMR(400MHz,DMSO-d6)δ11.07(s,1H),9.32(s,1H),8.09(s,1H),7.94(d,J＝6.3Hz,1H),7.90(s,1H),7.82(dd,J＝28.1,7.8Hz,2H),7.63–7.49(m,3H),5.17(dd,J＝13.2,5.0Hz,1H),4.57–4.41(m,4H),4.28(s,2H),3.27(s,8H),2.95(d,J＝12.8Hz,1H),2.67(d,J＝16.8Hz,1H),2.48(dd,J＝13.0,4.2Hz,1H),2.12–1.95(m,1H).LCMS(ESI)C 28 H 30 N 5 O 3 S + [M+H] + Calculated 516.21, found 516.3.
Example 230: preparation of 3- (5- ((4- ((5- (furan-2-yl) thiophen-2-yl) methyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05780)
The title compound (GT-05780) was prepared according to the method of scheme 1 (white solid, 20mg, yield 24.17%). 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),7.80(d,J＝7.9Hz,2H),7.72(d,J＝1.3Hz,2H),7.27(t,J＝14.3Hz,2H),6.78(d,J＝3.2Hz,1H),6.60(dd,J＝3.4,1.8Hz,1H),5.13(dd,J＝13.2,5.1Hz,1H),4.43(dd,J＝51.4,17.6Hz,6H),3.27–2.98(m,7H),2.99–2.87(m,2H),2.61(d,J＝16.9Hz,1H),2.42(dd,J＝13.1,4.5Hz,1H),2.05–1.96(m,1H).LCMS(ESI)C 27 H 29 N 4 O 4 S + [M+H] + Calculated 505.19, found 505.2.
Example 231: preparation of 3- (5- ((4- ((4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -1, 4-diazepan-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05504)
The title compound (GT-05504) was prepared according to the method of scheme 1 (white solid, 5mg, yield 5.57%). 1 H NMR(400MHz,DMSO-d6)δ11.59(s,1H),11.01(s,1H),10.51(s,1H),7.75(dd,J＝45.0,28.0Hz,3H),7.34–7.11(m,4H),5.14(d,J＝8.9Hz,1H),4.43(dd,J＝50.7,18.1Hz,4H),3.55(s,7H),3.32–2.74(m,5H),2.61(d,J＝17.6Hz,1H),2.37(dd,J＝55.3,18.4Hz,3H),2.03(d,J＝7.2Hz,4H),1.45(t,J＝6.1Hz,2H),0.95(s,6H).LCMS(ESI)C 34 H 42 FN 4 O 3 + [M+H] + Calculated 573.32, measured 573.3.
Example 232: preparation of 3- (5- (4- ((4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -1, 4-diazepan-1-carbonyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05505)
The title compound (GT-05505) (white solid, 25mg, yield 27.17%) was prepared according to the procedure of synthesis scheme 6 and example 76. 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),10.15(d,J＝44.9Hz,1H),7.85–7.75(m,1H),7.60(d,J＝16.5Hz,1H),7.51(t,J＝9.0Hz,1H),7.29–7.11(m,4H),5.14(dd,J＝13.2,4.8Hz,1H),4.42(ddd,J＝22.3,20.7,11.1Hz,2H),4.12–3.39(m,7H),3.29(s,2H),3.06–2.88(m,3H),2.61(d,J＝16.5Hz,1H),2.39(dt,J＝37.5,16.4Hz,4H),2.04(d,J＝14.1Hz,3H),1.47(dd,J＝14.5,8.2Hz,2H),0.96(dd,J＝12.5,5.3Hz,6H).LCMS(ESI)C 34 H 40 FN 4 O 4 + [M+H] + Calculated 587.30, found 587.3.
Example 233: preparation of 3- (5- ((7- ((4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05506)
The title compound (GT-05506) was prepared according to the method of scheme 1 (white solid, 20mg, yield 22.88%). 1 H NMR(400MHz,DMSO-d6)δ11.82(d,J＝5.3Hz,1H),11.01(s,1H),9.91(s,1H),7.83(s,1H),7.78(d,J＝7.8Hz,1H),7.72(t,J＝7.8Hz,1H),7.23–7.10(m,4H),5.13(dd,J＝13.2,5.0Hz,1H),4.58–4.30(m,4H),3.97–3.66(m,4H),3.47(s,2H),3.36(s,3H),3.34–3.30(m,2H),3.19(t,J＝13.8Hz,2H),2.91(d,J＝12.8Hz,1H),2.61(d,J＝15.9Hz,1H),2.43(dd,J＝13.2,4.5Hz,1H),2.35(d,J＝21.3Hz,3H),2.11(t,J＝11.9Hz,3H),2.02(s,3H),1.45(t,J＝6.2Hz,2H),0.95(s,6H).LCMS(ESI)C 36 H 44 FN 4 O 3 + [M+H] + Calculated 599.34, measured 599.3.
Example 234: preparation of 3- (5- (7- ((4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -2, 7-diazaspiro [3.5] nonane-2-carbonyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05507)
The title compound (GT-05507) (white solid, 19mg, yield 21.17%) was prepared according to the procedure of synthesis scheme 6 and example 76. 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),9.86(d,J＝32.0Hz,1H),7.84(d,J＝4.4Hz,1H),7.78(d,J＝7.9Hz,1H),7.73(d,J＝13.5Hz,1H),7.24–7.08(m,4H),5.24–5.03(m,1H),4.42(dd,J＝33.4,8.7Hz,2H),4.04(s,1H),3.95(d,J＝5.9Hz,1H),3.77(d,J＝7.2Hz,2H),3.51(d,J＝5.2Hz,2H),3.18(s,2H),2.92(t,J＝14.0Hz,1H),2.61(d,J＝15.8Hz,3H),2.33(s,3H),2.20–1.89(m,8H),1.46(s,2H),0.96(d,J＝3.6Hz,6H).LCMS(ESI)C 36 H 42 FN 4 O 4 + [M+H] + Calculated value 613.32, found 613.4.
Example 235: preparation of 3- (5- ((6- ((4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05670)
The title compound (GT-05670) was prepared according to the method of scheme 1 (white solid, 6mg, yield 11.27%). 1 H NMR(400MHz,DMSO-d6)δ11.43(s,1H),11.11(s,1H),11.00(s,1H),7.92–7.51(m,3H),7.23–7.14(m,4H),5.13(dd,J＝13.3,5.0Hz,1H),4.46–4.04(m,7H),3.87(s,2H),3.66(d,J＝49.0Hz,3H),2.93(dd,J＝21.6,9.0Hz,2H),2.61(d,J＝17.0Hz,1H),2.41(dd,J＝17.6,8.8Hz,1H),2.21(d,J＝31.5Hz,2H),2.03(d,J＝12.7Hz,3H),1.44(d,J＝21.9Hz,2H),0.95(d,J＝10.6Hz,6H).LCMS(ESI)C 34 H 40 FN 4 O 3 + [M+H] + Calculated 571.31, found 571.3.
Example 236: preparation of 3- (5- (6- ((4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -2, 6-diazaspiro [3.3] heptane-2-carbonyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05508)
The title compound (GT-05508) was prepared according to the procedure for synthesis scheme 6 and example 76 (white solid, 26mg, yield 28.17%). 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),7.91–7.65(m,3H),7.32–7.13(m,4H),5.14(dd,J＝13.2,5.0Hz,1H),4.62–4.36(m,3H),4.06(d,J＝26.1Hz,4H),3.60(s,2H),3.42(s,2H),3.09–2.84(m,2H),2.61(d,J＝17.1Hz,1H),2.45–2.35(m,1H),2.13(s,2H),2.03(s,3H),1.43(dd,J＝13.4,7.3Hz,2H),0.96(d,J＝7.7Hz,6H).LCMS(ESI)C 34 H 38 FN 4 O 4 + [M+H] + Calculated 585.29, measured 585.3.
Example 237: preparation of 3- (5- ((6- ((4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05509)
The title compound (GT-05509) was prepared according to the procedure of scheme 1 (white solid, 16mg, 17.38% yield). 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),9.12(s,1H),8.12–7.37(m,3H),7.33–7.07(m,4H),5.13(dd,J＝13.1,4.7Hz,1H),4.61–4.25(m,3H),3.73(d,J＝55.5Hz,2H),3.42(s,2H),3.34–3.18(m,2H),3.10–2.82(m,2H),2.61(d,J＝16.2Hz,2H),2.42(d,J＝9.0Hz,1H),2.23(s,3H),2.04(d,J＝15.1Hz,4H),1.43(t,J＝13.5Hz,2H),0.96(d,J＝4.6Hz,6H).LCMS(ESI)C 34 H 40 FN 4 O 3 + [M+H] + Calculated 571.31, found 571.3.
Example 238: preparation of 3- (5- (6- ((4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptane-3-carbonyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05671)
The title compound (GT-05671) (white solid, 6mg, yield 10.17%) was prepared according to the procedure of synthesis scheme 6 and example 76. 1 H NMR(400MHz,DMSO-d6)δ11.14(s,1H),11.02(s,1H),10.05(s,1H),7.81(dd,J＝19.4,7.9Hz,1H),7.74–7.58(m,1H),7.52(s,1H),7.23(dd,J＝11.3,5.5Hz,4H),5.30–5.01(m,1H),4.46(ddd,J＝32.6,22.2,14.0Hz,3H),4.13(t,J＝29.2Hz,2H),3.73(dd,J＝69.2,45.2Hz,6H),2.94(dd,J＝22.3,9.0Hz,2H),2.62(d,J＝16.8Hz,1H),2.45(d,J＝12.8Hz,1H),2.19(s,3H),2.05(s,3H),1.82(d,J＝8.5Hz,1H),1.44(s,2H),0.95(d,J＝9.7Hz,6H).LCMS(ESI)C 34 H 38 FN 4 O 4 + [M+H] + Calculated 585.29, measured 585.3.
Example 239: preparation of 3- (5- ((8- ((4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -3, 8-diazabicyclo [3.2.1] octane-3-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05510)
The title compound (GT-05510) was prepared according to the method of scheme 1 (white solid, 35mg, yield 39.17%). 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),7.96–7.57(m,3H),7.38–7.08(m,4H),5.13(dd,J＝13.3,5.1Hz,1H),4.41(dd,J＝52.1,17.6Hz,2H),4.14(s,2H),3.88(s,3H),3.52–3.43(m,3H),2.94(ddd,J＝30.5,23.6,17.6Hz,3H),2.61(d,J＝16.6Hz,1H),2.50–2.35(m,3H),2.19–1.95(m,5H),1.47(t,J＝6.2Hz,2H),1.23(s,2H),0.96(s,6H).LCMS(ESI)C 35 H 42 FN 4 O 3 + [M+H] + Calculated 585.32, measured 585.4.
Example 240: preparation of 3- (5- (8- ((4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -3, 8-diazabicyclo [3.2.1] octane-3-carbonyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05511)
The title compound (GT-05511) (white solid, 50mg, yield 54.18%) was prepared according to the procedure of synthesis scheme 6 and example 76. 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),10.39(s,1H),7.80(d,J＝7.8Hz,1H),7.66(s,1H),7.52(d,J＝7.6Hz,1H),7.20(d,J＝7.3Hz,4H),5.14(d,J＝8.2Hz,1H),4.43(d,J＝31.5Hz,3H),3.93(s,2H),3.51(s,5H),2.97–2.86(m,1H),2.61(d,J＝17.2Hz,1H),2.40(d,J＝4.8Hz,3H),2.07(s,3H),1.63(s,1H),1.48(t,J＝6.0Hz,3H),1.26(d,J＝19.2Hz,1H),1.13(s,1H),0.96(s,6H).LCMS(ESI)C 35 H 40 FN 4 O 4 + [M+H] + Calculated 599.30, measured 599.3.
Example 241: preparation of 3- (5- ((5- ((4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -2, 5-diazabicyclo [2.2.2] octane-2-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05512)
The title compound (GT-05512) was prepared according to the method of scheme 1 (white solid, 23mg, yield 25.84%). 1 H NMR(400MHz,DMSO-d6)δ11.45(d,J＝145.6Hz,1H),11.02(s,1H),7.74(dd,J＝19.1,11.3Hz,3H),7.21(s,4H),5.14(dd,J＝13.2,4.9Hz,1H),4.44(ddd,J＝51.7,23.0,12.1Hz,5H),3.63(d,J＝64.0Hz,6H),2.92(dd,J＝21.7,9.2Hz,3H),2.62(d,J＝16.6Hz,1H),2.47–2.27(m,3H),2.24–1.89(m,5H),1.65–1.26(m,3H),0.96(s,6H).LCMS(ESI)C 35 H 42 FN 4 O 3 + [M+H] + Calculated 585.32, measured 585.3.
Example 242: preparation of 3- (5- (5- ((4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -2, 5-diazabicyclo [2.2.2] octane-2-carbonyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05513)
Reference to Synthesis scheme 6 The procedure of example 76 was used to prepare the title compound (GT-05513) (white solid, 14mg, yield 25.16%). 1 H NMR(400MHz,DMSO-d6)δ11.02(d,J＝8.8Hz,1H),10.34(d,J＝115.5Hz,1H),7.79(dt,J＝14.1,7.1Hz,1H),7.64–7.46(m,1H),7.28–7.12(m,4H),5.14(dd,J＝13.2,3.2Hz,1H),4.57–4.33(m,2H),3.93–3.48(m,6H),3.24–2.79(m,4H),2.61(d,J＝17.0Hz,1H),2.44–2.13(m,4H),2.08–1.92(m,3H),1.88–1.66(m,2H),1.47(dd,J＝13.1,6.6Hz,2H),0.96(dd,J＝10.4,4.0Hz,6H).LCMS(ESI)C 35 H 40 FN 4 O 4 + [M+H] + Calculated 599.30, measured 599.3.
Example 243: preparation of 3- (5- ((6- (4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) -2, 6-diazaspiro [3.3] heptane-2-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05664)
The title compound (GT-05664) was prepared according to the method of scheme 1 (white solid, 12mg, 16.85% yield). 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),7.77(d,J＝7.7Hz,1H),7.66(s,1H),7.56(s,1H),7.27(ddd,J＝12.2,8.8,5.6Hz,2H),7.21–7.12(m,2H),5.13(dd,J＝13.3,5.0Hz,1H),4.41(dd,J＝51.5,17.5Hz,4H),4.07–3.53(m,6H),3.36(s,2H),3.33–3.30(m,1H),3.05–2.86(m,1H),2.61(d,J＝16.8Hz,1H),2.47–2.37(m,1H),2.23(s,2H),2.12(s,1H),2.07–1.97(m,1H),1.39(t,J＝6.3Hz,2H),0.97(s,6H).LCMS(ESI)C 34 H 38 FN 4 O 4 + [M+H] + Calculated 585.29, measured 585.3.
Example 244: preparation of 3- (5- ((3- (4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) -3, 6-diazabicyclo [3.1.1] heptane-6-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05514)
The title compound (GT-05514) was prepared according to the method of scheme 1 (white solid, 16mg, yield 18.00%). 1 H NMR(400MHz,DMSO-d6)δ11.49(s,1H),11.01(s,1H),9.99(d,J＝268.4Hz,1H),7.93–7.69(m,2H),7.49–7.05(m,5H),5.13(dd,J＝13.2,4.9Hz,1H),4.73–4.13(m,5H),4.11–3.38(m,4H),3.26–2.79(m,3H),2.61(d,J＝16.7Hz,1H),2.32(ddd,J＝49.8,33.9,19.3Hz,5H),2.07–1.87(m,2H),1.45(d,J＝6.1Hz,2H),1.05–0.95(m,6H).LCMS(ESI)C 34 H 38 FN 4 O 4 + [M+H] + Calculated 585.29, measured 585.3.
Example 245: preparation of 3- (5- ((6- (4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05515)
The title compound (GT-05515) was prepared according to the method of scheme 1 (white solid, 13mg, 14.61% yield). 1 H NMR(400MHz,DMSO-d6)δ11.88(s,1H),11.01(s,1H),7.93(s,1H),7.81(s,2H),7.31–7.17(m,4H),5.15(dd,J＝13.2,5.0Hz,1H),4.40(dt,J＝50.3,25.0Hz,4H),3.97(d,J＝121.6Hz,2H),3.52(s,5H),2.99–2.86(m,1H),2.65(t,J＝27.7Hz,2H),2.48–2.37(m,1H),2.23(d,J＝16.1Hz,2H),1.99(t,J＝14.6Hz,2H),1.78(d,J＝19.3Hz,1H),1.60(d,J＝8.2Hz,1H),1.44–1.33(m,2H),1.00–0.90(m,6H).LCMS(ESI)C 34 H 38 FN 4 O 4 + [M+H] + Calculated 585.29, measured 585.3.
Example 246: preparation of 3- (5- ((3- (4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) -3, 8-diazabicyclo [3.2.1] octane-8-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05516)
The title compound (GT-05516) was prepared according to the method of scheme 1 (white solid, 30mg, 34.00% yield). 1 H NMR(400MHz,DMSO-d6)δ11.82(s,1H),11.01(s,1H),10.82(s,1H),7.79(d,J＝6.4Hz,3H),7.39(s,1H),7.16(dd,J＝20.7,15.7Hz,3H),5.13(dd,J＝13.2,4.8Hz,1H),4.46(s,4H),3.80(s,4H),3.39–3.26(m,2H),3.05–2.79(m,2H),2.61(d,J＝17.0Hz,1H),2.43(d,J＝8.4Hz,4H),2.06–1.83(m,3H),1.43(d,J＝4.8Hz,3H),0.96(d,J＝8.0Hz,6H).LCMS(ESI)C 35 H 40 FN 4 O 4 + [M+H] + Calculated 599.30, measured 599.4.
Example 247: preparation of 3- (5- ((8- (4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) -3, 8-diazabicyclo [3.2.1] octane-3-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05517)
The title compound (GT-05517) was prepared according to the procedure of FIG. 1 (white solid, 40mg, 45.75% yield). 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),10.87(s,1H),7.86(d,J＝70.5Hz,3H),7.30–7.05(m,4H),5.13(dd,J＝13.2,3.3Hz,1H),4.39(dt,J＝32.3,16.0Hz,5H),3.91(s,1H),3.60(s,2H),3.19–2.83(m,4H),2.61(d,J＝17.2Hz,1H),2.41(ddd,J＝39.4,19.7,15.4Hz,4H),2.09–1.80(m,4H),1.44(dd,J＝13.2,6.5Hz,2H),1.30–1.08(m,1H),0.98(d,J＝9.7Hz,6H).LCMS(ESI)C 35 H 40 FN 4 O 4 + [M+H] + Calculated 599.30, measured 599.3.
Example 248: preparation of 3- (5- ((3- (4 '-chloro- [1,1' -biphenyl ] -2-carbonyl) -3, 6-diazabicyclo [3.1.1] heptane-6-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05665)
The title compound (GT-05665) was prepared according to the method of scheme 1 (white solid, 35mg, yield 48.10%). 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),9.78(s,1H),8.01–7.13(m,11H),5.24–5.08(m,1H),4.70–4.15(m,4H),3.87(s,2H),3.60(s,2H),3.33–3.11(m,2H),2.92(ddd,J＝13.4,11.7,5.0Hz,1H),2.61(d,J＝16.2Hz,1H),2.48–2.11(m,2H),2.02(s,1H).LCMS(ESI)C 32 H 30 ClN 4 O 4 + [M+H] + Calculated 569.20, measured 569.2.
Example 249: preparation of 3- (5- ((3- (4 '-chloro- [1,1' -biphenyl ] -2-carbonyl) -3, 6-diazabicyclo [3.1.1] heptan-6-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05666)
The title compound (GT-05666) was prepared according to the method of scheme 1 (white solid, 45mg, yield 60.12%). 1 H NMR(400MHz,DMSO-d6)δ11.02(d,J＝4.8Hz,1H),9.83(s,1H),7.64–7.22(m,10H),5.14(dd,J＝13.2,5.0Hz,1H),4.80–4.29(m,4H),3.67(dd,J＝67.6,63.5Hz,3H),3.33–2.85(m,4H),2.61(d,J＝16.3Hz,1H),2.42(dd,J＝30.1,25.2Hz,2H),2.22–1.94(m,2H).LCMS(ESI)C 32 H 29 ClFN 4 O 4 + [M+H] + Calculated value 587.19, measured value 587.2。
Example 250: preparation of 3- (5- ((3- (4 '-chloro- [1,1' -biphenyl ] -2-carbonyl) -3, 6-diazabicyclo [3.1.1] heptane-6-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05667)
The title compound (GT-05667) was prepared according to the method of scheme 1 (white solid, 35mg, yield 46.35%). 1 H NMR(400MHz,DMSO-d6)δ11.02(d,J＝4.7Hz,1H),9.84(s,1H),7.62–7.31(m,10H),5.18–5.05(m,1H),4.75–4.24(m,4H),4.08–3.46(m,3H),3.31–2.84(m,4H),2.61(d,J＝15.9Hz,1H),2.48–2.31(m,2H),2.03(d,J＝5.0Hz,2H).LCMS(ESI)C 32 H 29 ClFN 4 O 4 + [M+H] + Calculated 587.19, found 587.2.
Example 251: preparation of 3- (5- ((3- (4 '-chloro- [1,1' -biphenyl ] -2-carbonyl) -3, 6-diazabicyclo [3.1.1] heptan-6-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05668)
The title compound (GT-05668) was prepared according to the method of scheme 1 (white solid, 20mg, yield 26.64%). 1 H NMR(400MHz,DMSO-d6)δ11.02(d,J＝2.7Hz,1H),10.72–9.49(m,1H),7.68–7.35(m,10H),5.19–5.02(m,1H),4.81–4.31(m,4H),4.16–3.42(m,4H),3.33–2.86(m,4H),2.61(d,J＝16.4Hz,1H),2.47–2.24(m,2H),2.01(s,1H).LCMS(ESI)C 32 H 29 ClFN 4 O 4 + [M+H] + Calculated 587.19, found 587.2.
Example 252: preparation of 3- (5- ((6- (4 '-chloro- [1,1' -biphenyl ] -2-carbonyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05669)
The title compound (GT-05669) (white solid, 40mg, yield 55.10%) was prepared according to the method of scheme 1. 1 H NMR(400MHz,DMSO-d6)δ11.84(s,1H),11.02(d,J＝5.8Hz,1H),7.87(d,J＝38.8Hz,3H),7.57(d,J＝8.3Hz,3H),7.49–7.39(m,4H),7.30(dd,J＝46.2,7.2Hz,1H),5.16(ddd,J＝13.5,8.8,5.0Hz,1H),4.57–4.26(m,5H),3.64(d,J＝83.3Hz,4H),2.93(t,J＝12.6Hz,1H),2.77(s,1H),2.62(d,J＝17.0Hz,1H),2.45(d,J＝13.2Hz,1H),2.30(s,1H),2.09–1.87(m,2H).LCMS(ESI)C 32 H 30 ClN 4 O 4 + [M+H] + Calculated 569.20, measured 569.3.
Example 253: preparation of 3- (4- (4- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) piperazine-1-carbonyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05486)
The title compound (GT-05486) (white solid, 8mg, yield 213.32%) was prepared according to the method of scheme 1. 1 H NMR(400MHz,DMSO-d6)δ11.07(s,1H),10.99(s,1H),8.09(s,1H),7.83(d,J＝7.1Hz,1H),7.66–7.29(m,9H),5.13(dd,J＝13.3,5.0Hz,1H),4.39(dd,J＝40.4,17.8Hz,4H),3.61(s,3H),3.26(s,3H),3.06–2.72(m,3H),2.59(d,J＝17.1Hz,1H),2.38(dt,J＝17.5,6.8Hz,1H),1.98(dd,J＝11.5,6.2Hz,1H).LCMS(ESI)C 31 H 30 ClN 4 O 4 + [M+H] + Calculated 557.20, found 557.2.
Example 254: preparation of 5- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazine-1-carbonyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-05366)
The title compound (GT-05366) (white solid, 13mg, yield 30.80%) was prepared according to the procedure of synthesis scheme 6 and example 76. 1 H NMR(400MHz,DMSO)δ11.15(s,1H),10.14(s,1H),8.11–7.93(m,2H),7.88(d,J＝7.2Hz,1H),7.47(d,J＝7.7Hz,2H),7.15(d,J＝7.9Hz,2H),5.19(dd,J＝12.7,5.3Hz,1H),4.46(s,1H),3.59(s,4H),3.21–3.07(m,1H),3.03–2.85(m,2H),2.75–2.56(m,3H),2.55(d,J＝6.9Hz,1H),2.10–1.96(m,3H),1.47(s,2H),1.26(dd,J＝14.6,8.2Hz,1H),0.96(s,6H).LCMS(ESI)C 33 H 36 ClN 4 O 5 + [M+H] + Calculated 603.24, measured 603.3.
Example 255: preparation of 5- (3- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptane-6-carbonyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-05369)
The title compound (GT-05369) (white solid, 10mg, yield 23.26%) was prepared according to the procedure of FIG. 6 and example 76)。 1 H NMR(400MHz,DMSO)δ11.16(s,1H),10.83(s,1H),8.01(d,J＝7.0Hz,2H),7.83(d,J＝34.1Hz,1H),7.46(s,2H),7.12(d,J＝6.5Hz,2H),5.21(s,1H),4.49(s,2H),3.62(s,3H),2.90(d,J＝13.4Hz,2H),2.80(s,1H),2.65(s,1H),2.60(s,2H),2.41(s,1H),2.33(s,2H),2.05(s,3H),1.93(s,1H),1.45(s,2H),0.95(s,6H),0.82(s,1H).LCMS(ESI)C 34 H 36 ClN 4 O 5 + [M+H] + Calculated 615.24, measured 615.3.
Example 256: preparation of 5- ((1R, 4R) -5- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -2, 5-diazabicyclo [2.2.1] heptane-2-carbonyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-05410)
The title compound (GT-05410) (white solid, 4.6mg, yield 10.70%) was prepared according to the procedure of synthesis scheme 6 and example 76. 1 H NMR(400MHz,DMSO)δ11.15(s,1H),7.99(d,J＝31.7Hz,3H),7.55–7.37(m,2H),7.19(d,J＝7.6Hz,2H),5.19(d,J＝8.2Hz,1H),4.30(s,1H),3.89(s,1H),3.74(s,2H),3.62(s,2H),3.13(s,1H),2.89(d,J＝12.4Hz,2H),2.30(d,J＝25.2Hz,2H),2.06(s,3H),1.45(s,3H),1.29–1.24(m,1H),0.96(s,6H).LCMS(ESI)C 34 H 36 ClN 4 O 5 + [M+H] + Calculated 615.24, measured 615.3.
Example 257: preparation of 5- ((1S, 4S) -5- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -2, 5-diazabicyclo [2.2.1] heptane-2-carbonyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-05411)
The title compound (GT-05411) (white solid, 6.7mg, yield 31.16%) was prepared according to the procedure of synthesis scheme 6 and example 76. 1 H NMR(400MHz,DMSO)δ11.15(s,1H),8.04(d,J＝9.1Hz,2H),7.94(d,J＝8.3Hz,1H),7.45(dd,J＝18.3,8.0Hz,2H),7.17(dd,J＝14.0,7.8Hz,2H),5.19(dd,J＝12.6,5.0Hz,1H),3.75(s,2H),3.59(d,J＝22.6Hz,2H),3.11(d,J＝11.2Hz,1H),2.93(d,J＝17.3Hz,1H),2.69–2.56(m,2H),2.31(d,J＝11.1Hz,2H),2.05(d,J＝11.7Hz,4H),1.45(s,3H),1.29–1.22(m,1H),0.97(s,6H).LCMS(ESI)C 34 H 36 ClN 4 O 5 + [M+H] + Calculated 615.24, measured 615.3.
Example 258: preparation of 5- (8- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -3, 8-diazabicyclo [3.2.1] octane-3-carbonyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-05412)
The title compound (GT-05412) (white solid, 13.7mg, yield 31.19%) was prepared according to the procedure of synthesis scheme 6 and example 76. 1 H NMR(400MHz,DMSO)δ11.14(s,1H),10.19(s,1H),8.00(d,J＝7.9Hz,2H),7.89(d,J＝7.5Hz,1H),7.44(d,J＝8.2Hz,2H),7.18(d,J＝8.2Hz,2H),5.19(dd,J＝12.8,5.4Hz,1H),3.92(s,2H),3.62(s,1H),3.51(s,1H),2.96–2.85(m,1H),2.59(dd,J＝23.2,11.4Hz,2H),2.37(s,2H),2.07(s,3H),1.66(d,J＝27.4Hz,2H),1.48(s,3H),1.30–1.20(m,2H),1.14(s,1H),0.96(s,6H).LCMS(ESI)C 35 H 38 ClN 4 O 5 + [M+H] + Calculated 629.25, measured 629.3.
Example 259: preparation of 2- (2, 6-dioxopiperidin-3-yl) -5- (4- ((4 '-fluoro-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazine-1-carbonyl) isoindoline-1, 3-dione (GT-05413)
The title compound (GT-05413) (white solid, 15.1mg, yield 38.45%) was prepared according to the procedure of synthesis scheme 6 and example 76. 1 H NMR(400MHz,DMSO)δ11.14(s,1H),9.85(s,1H),8.06–7.93(m,2H),7.88(d,J＝7.7Hz,1H),7.21(dt,J＝14.2,8.4Hz,4H),5.19(dd,J＝12.7,5.4Hz,1H),4.45(s,1H),3.58(d,J＝18.0Hz,4H),3.38(s,1H),3.32–3.16(m,2H),2.98–2.81(m,2H),2.76–2.53(m,3H),2.28(d,J＝28.8Hz,4H),2.11–2.03(m,1H),1.73(d,J＝22.6Hz,4H).LCMS(ESI)C 31 H 32 FN 4 O 5 + [M+H] + Calculated 559.24, measured 559.3.
Example 260: preparation of 5- (5- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -2, 5-diazabicyclo [2.2.2] octane-2-carbonyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-05414)
The title compound (GT-05414) (white solid, 10.7mg,yield 24.36%). 1 H NMR(400MHz,DMSO)δ11.14(s,1H),8.01(dd,J＝29.6,21.8Hz,2H),7.87(s,1H),7.55–7.43(m,2H),7.29–7.06(m,3H),5.19(d,J＝13.3Hz,1H),3.72(d,J＝25.5Hz,4H),2.94(dd,J＝44.0,11.5Hz,3H),2.61(d,J＝18.5Hz,2H),2.34–2.16(m,3H),2.12–2.02(m,3H),1.91(s,1H),1.62(d,J＝15.3Hz,1H),1.48(d,J＝7.1Hz,2H),1.26(t,J＝6.7Hz,1H),0.95(s,6H).LCMS(ESI)C 35 H 38 ClN 4 O 5 + [M+H] + Calculated 629.25, measured 629.3.
Example 261: preparation of 2- (2, 6-dioxopiperidin-3-yl) -5- (4- (4 '-fluoro-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) piperazine-1-carbonyl) isoindoline-1, 3-dione (GT-05415)
The title compound (GT-05415) (white solid, 18mg, yield 47.63%) was prepared according to the procedure of synthesis scheme 6 and example 76. 1 H NMR(400MHz,DMSO)δ11.14(s,1H),7.96(d,J＝7.6Hz,1H),7.88(s,1H),7.81(d,J＝7.3Hz,1H),7.29(s,2H),7.16(s,2H),5.18(dd,J＝12.8,5.3Hz,1H),3.52(s,1H),3.13(d,J＝33.7Hz,4H),2.89(dd,J＝20.0,10.0Hz,1H),2.68–2.54(m,3H),2.33(s,1H),2.14–1.96(m,3H),1.65(d,J＝41.0Hz,5H),1.32–1.17(m,1H),1.14–0.98(m,1H).LCMS(ESI)C 31 H 30 FN 4 O 6 + [M+H] + Calculated 573.21, measured 573.3.
Example 262: preparation of 2- (2, 6-dioxopiperidin-3-yl) -5- (3- (4 '-fluoro-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) -3, 6-diazabicyclo [3.1.1] heptane-6-carbonyl) isoindoline-1, 3-dione (GT-05416)
The title compound (GT-05416) was prepared according to the procedure for synthesis scheme 6 and example 76 (white solid, 10mg, yield 25.85%). 1 H NMR(400MHz,DMSO)δ11.15(s,1H),8.00(s,2H),7.81–7.63(m,1H),7.30(s,2H),7.11(t,J＝25.6Hz,2H),5.19(d,J＝12.4Hz,1H),4.57–4.24(m,2H),3.41(s,1H),3.31–3.24(m,2H),3.08(s,1H),2.89(d,J＝14.0Hz,1H),2.71–2.52(m,4H),2.33(s,1H),2.09(s,3H),1.63(t,J＝44.0Hz,5H).LCMS(ESI)C 32 H 30 FN 4 O 6 + [M+H] + Calculated 585.21, measured 585.3.
Example 263: preparation of 3- (5- ((4- (4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) piperazin-1-yl) amino) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05417)
The title compound (GT-05417) (white solid, 33mg, yield 46.61%) was prepared according to the method of FIG. 6. 1 H NMR(400MHz,DMSO)δ10.92(s,1H),7.45–7.35(m,3H),7.25(d,J＝8.5Hz,2H),6.87(s,1H),6.79(d,J＝8.3Hz,1H),5.01(dd,J＝13.2,5.1Hz,1H),4.27(d,J＝17.1Hz,1H),4.14(d,J＝16.9Hz,1H),3.50–3.33(m,4H),2.91–2.82(m,1H),2.57(d,J＝18.2Hz,4H),2.39(s,1H),2.40–2.28(m,3H),2.13(s,1H),1.98–1.86(m,2H),1.46(d,J＝9.7Hz,2H),0.98(s,6H).LCMS(ESI)C 32 H 37 ClN 5 O 4 + [M+H] + Calculated 590.25, measured 590.3.
Example 264: preparation of 3- (5- ((1- (4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) piperidin-4-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05418)
The title compound (GT-05418) was prepared according to the method of FIG. 6 (white solid, 10mg, 15.01% yield). 1 H NMR(400MHz,DMSO)δ10.98(s,1H),7.62(d,J＝7.6Hz,1H),7.46(d,J＝8.5Hz,1H),7.41–7.19(m,4H),7.19–7.14(m,1H),5.10(dd,J＝13.0,4.9Hz,1H),4.42(d,J＝17.2Hz,1H),4.33–4.08(m,2H),3.43(d,J＝13.0Hz,2H),3.32–3.28(m,1H),2.92–2.86(m,1H),2.75(d,J＝12.6Hz,1H),2.65–2.55(m,2H),2.36(dt,J＝31.3,20.7Hz,5H),2.20–2.11(m,1H),1.97(dd,J＝16.6,11.1Hz,2H),1.58(s,1H),1.42(d,J＝5.3Hz,3H),0.97(s,6H).LCMS(ESI)C 34 H 39 ClN 3 O 4 + [M+H] + Calculated 588.26, measured 588.3.
Example 265: preparation of 3- (5- ((1- (4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) azetidin-3-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05419)
The title compound (GT-05419) was prepared according to the method of FIG. 6 (white solid, 16mg, yield 25.28%). 1 H NMR(400MHz,DMSO)δ10.98(s,1H),7.62(d,J＝7.7Hz,1H),7.47(dd,J＝8.6,2.5Hz,2H),7.30(d,J＝8.5Hz,2H),7.22(s,1H),7.15(d,J＝7.8Hz,1H),5.10(dd,J＝13.1,4.8Hz,1H),4.46–4.19(m,2H),3.78–3.60(m,2H),3.26(dd,J＝9.9,4.4Hz,1H),3.04–2.97(m,1H),2.90(d,J＝12.2Hz,1H),2.58(t,J＝13.9Hz,3H),2.54(s,1H),2.46–2.37(m,2H),2.27(s,1H),2.21(d,J＝17.5Hz,2H),2.01(dd,J＝19.2,11.6Hz,2H),1.39(t,J＝6.4Hz,2H),0.95(s,6H).LCMS(ESI)C 32 H 35 ClN 3 O 4 + [M+H] + Calculated 560.23, measured 560.2.
Example 266: preparation of 3- (5- ((1- (4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) azetidin-3-ylmethylene) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05420)
The title compound (GT-05420) was prepared according to the method of FIG. 6 (white solid, 18mg, yield 28.46%). 1 H NMR(400MHz,DMSO)δ10.98(d,J＝5.9Hz,1H),7.66(dd,J＝11.3,7.9Hz,1H),7.41–7.34(m,2H),7.32–7.26(m,2H),7.20(dd,J＝20.1,9.7Hz,1H),6.41(d,J＝16.4Hz,1H),5.11(dd,J＝12.4,6.8Hz,1H),4.74–4.45(m,2H),4.45–4.27(m,3H),2.89(dd,J＝11.6,6.0Hz,1H),2.60(d,J＝16.4Hz,3H),2.42–2.29(m,3H),2.14(s,2H),2.00(d,J＝5.0Hz,1H),1.46–1.41(m,1H),0.98(s,6H).LCMS(ESI)C 32 H 33 ClN 3 O 4 + [M+H] + Calculated 558.22, measured 558.3.
Example 267: preparation of 3- (5- ((1- (4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) -3-hydroxyazetidin-3-yl) (hydroxy) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05426)
The title compound (GT-05426) was prepared according to the method of FIG. 6 (white solid, 27mg, 40.24% yield). 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),7.63(dd,J＝7.8,2.8Hz,1H),7.59–7.32(m,4H),7.27(dd,J＝11.8,8.5Hz,2H),5.72(s,1H),5.11(dd,J＝13.3,4.9Hz,1H),4.43(dd,J＝17.1,5.5Hz,1H),4.35–4.16(m,2H),3.89(t,J＝10.6Hz,1H),3.65(d,J＝9.2Hz,1H),3.33–3.17(m,2H),2.99–2.86(m,1H),2.60(d,J＝16.9Hz,1H),2.48–2.30(m,1H),2.22–1.97(m,4H),1.39(d,J＝5.3Hz,2H),0.79(s,6H).LCMS(ESI)C 32 H 35 ClN 3 O 6 + [M+H] + Calculated 592.22, measured 592.3.
Example 268: preparation of 3- (5- ((1- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -3-hydroxyazetidin-3-yl) (hydroxy) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05427)
The title compound (GT-05427) was prepared according to the method of FIG. 4 (white solid, 17mg, 13.76% yield). 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),10.26(s,1H),7.67(dd,J＝7.8,4.6Hz,1H),7.61–7.50(m,2H),7.44(t,J＝7.1Hz,1H),7.24(d,J＝8.3Hz,1H),7.21–7.11(m,1H),6.24–6.18(m,1H),5.12(d,J＝13.2Hz,1H),4.41(ddd,J＝38.6,16.2,9.0Hz,3H),4.03(dd,J＝27.4,5.4Hz,1H),3.72(d,J＝5.4Hz,1H),3.65–3.40(m,2H),2.98–2.85(m,1H),2.57(dd,J＝25.9,10.7Hz,2H),2.40(d,J＝13.4Hz,1H),2.15(d,J＝19.5Hz,2H),2.03(t,J＝20.7Hz,3H),1.43(d,J＝6.4Hz,2H),0.87(s,6H).LCMS(ESI)C 32 H 37 ClN 3 O 5 + [M+H] + Calculated 578.24, measured 578.2.
Example 269: preparation of 3- (5- ((1- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) azetidin-3-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05428)
The title compound (GT-05428) was prepared according to the method of FIG. 4 (white solid, 4mg, yield 4.26%). 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),7.66(dd,J＝7.7,2.9Hz,1H),7.50–7.40(m,3H),7.33(d,J＝10.9Hz,1H),7.18(ddd,J＝22.2,15.1,8.2Hz,3H),5.11(dd,J＝13.2,5.1Hz,1H),4.43(d,J＝17.4Hz,1H),4.30(d,J＝17.5Hz,1H),4.03(s,1H),3.82(d,J＝6.5Hz,1H),3.64(s,2H),3.58(d,J＝6.5Hz,1H),3.17(d,J＝8.3Hz,1H),3.02–2.85(m,2H),2.82(d,J＝7.6Hz,1H),2.62–2.54(m,2H),2.45–2.34(m,1H),2.16(s,2H),2.03(d,J＝11.2Hz,3H),1.46–1.38(m,2H),0.93(s,6H).LCMS(ESI)C 32 H 37 ClN 3 O 3 + [M+H] + Calculated 546.25, found 546.3.
Example 270: preparation of 3- (5- (8- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05429)
The title compound (GT-05429) (white solid, 8.5mg, yield 6.78%) was prepared according to the method of FIG. 4. 1 H NMR(400MHz,DMSO-d6)δ10.96(s,1H),10.20(s,1H),7.55(d,J＝8.5Hz,1H),7.46(dd,J＝13.4,8.5Hz,2H),7.25(d,J＝8.4Hz,2H),7.08–6.91(m,2H),5.05(dd,J＝13.2,5.0Hz,1H),4.27(dd,J＝50.8,17.0Hz,2H),3.91(s,2H),3.75(d,J＝12.1Hz,2H),3.60(d,J＝5.2Hz,1H),3.51(d,J＝12.2Hz,2H),2.89(dd,J＝21.6,9.5Hz,1H),2.70–2.53(m,2H),2.37(dd,J＝23.6,9.9Hz,3H),2.12(s,2H),2.02–1.82(m,2H),1.76(d,J＝8.3Hz,1H),1.50(dd,J＝15.3,9.3Hz,2H),1.33(s,1H),0.98(d,J＝12.9Hz,6H).LCMS(ESI)C 34 H 40 ClN 4 O 3 + [M+H] + Calculated 587.28, measured 587.3.
Example 271: preparation of 3- (5- (3- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -3, 8-diazabicyclo [3.2.1] octane-8-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05430)
The title compound (GT-05430) was prepared according to the method of FIG. 4 (white solid, 21mg, 16.75% yield). 1 H NMR(400MHz,DMSO-d6)δ10.97(s,1H),10.11(s,1H),7.58(d,J＝8.4Hz,1H),7.27(d,J＝8.3Hz,2H),7.06–6.99(m,3H),6.96(d,J＝8.7Hz,1H),5.10(dd,J＝13.2,4.9Hz,1H),4.50(s,2H),4.30(dd,J＝38.0,16.9Hz,2H),3.01(d,J＝10.6Hz,2H),2.84(dd,J＝24.4,12.5Hz,2H),2.60(d,J＝16.8Hz,1H),2.42(dd,J＝13.2,8.7Hz,1H),2.24(d,J＝8.0Hz,2H),2.08(d,J＝29.8Hz,4H),1.95(s,3H),1.36(d,J＝5.9Hz,2H),0.96(s,1H),0.84(d,J＝3.2Hz,6H).LCMS(ESI)C 34 H 40 ClN 4 O 3 + [M+H] + Calculated 587.28, measured 587.3.
Example 272: preparation of 3- (5- (3- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptane-6-carbonyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05440)
The title compound (GT-05440) (white solid, 14mg, yield 31.82%) was prepared according to the procedure of synthesis scheme 6 and example 76. 1 H NMR(400MHz,DMSO-d6)δ11.04(s,1H),10.61(s,1H),7.89–7.76(m,1H),7.60(s,1H),7.54–7.23(m,3H),7.11(d,J＝7.5Hz,2H),5.16(dd,J＝13.3,4.7Hz,1H),4.47(dd,J＝40.8,17.2Hz,3H),3.65(s,2H),3.53(s,1H),2.96–2.87(m,1H),2.77(s,1H),2.62(d,J＝17.3Hz,2H),2.45(s,2H),2.28(s,3H),2.02(d,J＝24.3Hz,3H),1.45(s,2H),0.96(s,6H).LCMS(ESI)C 34 H 38 ClN 4 O 4 + [M+H] + Calculated 601.26, found 601.3.
Example 273: preparation of 3- (5- ((1R, 4R) -5- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -2, 5-diazabicyclo [2.2.1] heptane-2-carbonyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05441)
The title compound (GT-05441) (white solid, 23mg, yield 52.28%) was prepared according to the procedure of synthesis scheme 6 and example 76. 1 H NMR(400MHz,DMSO-d6)δ11.03(s,1H),9.91(s,1H),7.82(d,J＝7.3Hz,2H),7.71(d,J＝8.9Hz,1H),7.50–7.42(m,2H),7.17(dd,J＝12.4,8.3Hz,2H),5.17–5.10(m,1H),4.48(dd,J＝31.3,18.2Hz,2H),4.39(s,1H),3.77(d,J＝10.9Hz,2H),3.66(s,1H),3.19–3.07(m,1H),3.04–2.88(m,2H),2.71–2.56(m,2H),2.42(d,J＝8.4Hz,1H),2.26(s,2H),2.03(d,J＝8.1Hz,3H),1.46(d,J＝6.6Hz,3H),0.95(s,6H).LCMS(ESI)C 34 H 38 ClN 4 O 4 + [M+H] + Calculated 601.26, found 601.3.
Example 274: preparation of 3- (5- ((1S, 4S) -5- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -2, 5-diazabicyclo [2.2.1] heptane-2-carbonyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05442)
The title compound (GT-05442) (white solid, 7mg, yield 15.91%) was prepared according to the procedure of synthesis scheme 6 and example 76. 1 H NMR(400MHz,DMSO-d6)δ11.03(s,1H),10.21(d,J＝58.5Hz,1H),7.85–7.76(m,2H),7.72(s,1H),7.51–7.44(m,2H),7.17(dd,J＝11.7,8.4Hz,2H),5.15(dd,J＝13.4,5.0Hz,1H),4.55–4.36(m,3H),3.68(d,J＝15.5Hz,3H),3.15(dd,J＝25.8,11.4Hz,1H),2.95(dd,J＝32.8,13.1Hz,2H),2.61(d,J＝15.7Hz,2H),2.41(s,1H),2.30(d,J＝27.9Hz,2H),2.03(s,3H),1.44(s,3H),0.95(s,6H).LCMS(ESI)C 34 H 38 ClN 4 O 4 + [M+H] + Calculated 601.26, found 601.3.
Example 275: preparation of 3- (5- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazine-1-carbonyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05445)
The title compound (GT-05445) (white solid, 25mg, yield 57.92%) was prepared according to the procedure of synthesis scheme 6 and example 76. 1 H NMR(400MHz,DMSO-d6)δ11.03(s,1H),9.28(s,1H),7.80(d,J＝7.8Hz,1H),7.65(s,1H),7.54(d,J＝7.6Hz,1H),7.46(d,J＝8.3Hz,2H),7.14(d,J＝8.3Hz,2H),5.14(dd,J＝13.3,5.1Hz,1H),4.47(s,1H),4.37(d,J＝17.7Hz,1H),3.61(s,3H),3.47(s,2H),3.17(s,2H),2.95–2.84(m,2H),2.61(d,J＝16.8Hz,1H),2.42(dd,J＝13.1,4.2Hz,1H),2.22(s,2H),2.01(d,J＝13.8Hz,3H),1.48(s,2H),0.97(s,6H).LCMS(ESI)C 33 H 38 ClN 4 O 4 + [M+H] + Calculated 589.26, found 589.3.
Example 276: preparation of 3- (5- (8- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -3, 8-diazabicyclo [3.2.1] octane-3-carbonyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05446)
The title compound (GT-05446) (white solid, 21mg, yield 46.71%) was prepared according to the procedure of synthesis scheme 6 and example 76. 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),9.93(s,1H),7.80(d,J＝7.8Hz,1H),7.67(s,1H),7.53(d,J＝7.5Hz,1H),7.44(d,J＝8.2Hz,2H),7.18(d,J＝8.2Hz,2H),5.14(dd,J＝13.3,5.1Hz,1H),4.49(d,J＝17.9Hz,1H),4.37(d,J＝17.8Hz,1H),3.88(d,J＝46.0Hz,2H),3.64(s,1H),3.51(s,3H),3.38(s,2H),2.93(dd,J＝22.1,9.3Hz,1H),2.58(dd,J＝24.1,11.3Hz,2H),2.42(dd,J＝13.1,4.5Hz,1H),2.34(s,2H),2.07(s,2H),2.03–1.96(m,1H),1.65(s,1H),1.48(s,3H),1.37–1.21(m,2H),1.16(s,1H),0.96(s,7H).LCMS(ESI)C 35 H 40 ClN 4 O 4 + [M+H] + Calculated 615.27, measured 615.3.
Example 277: preparation of 3- (5- (5- ((4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) octahydropyrrolo [3,4-c ] pyrrole-2-carbonyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05447)
The title compound (GT-05447) (white solid, 32mg, yield 48.44%) was prepared according to the procedure of synthesis scheme 6 and example 76. 1 H NMR(400MHz,DMSO-d6)δ11.02(s,1H),9.57(d,J＝62.2Hz,1H),7.80(d,J＝7.8Hz,1H),7.65–7.54(m,1H),7.22(t,J＝8.4Hz,2H),7.18–7.12(m,2H),5.15(dd,J＝13.3,4.9Hz,1H),4.51(d,J＝17.6Hz,1H),4.38(dd,J＝17.5,4.8Hz,1H),3.68(d,J＝5.0Hz,2H),3.55(d,J＝37.8Hz,4H),3.22–3.05(m,2H),3.00–2.90(m,2H),2.62(d,J＝18.0Hz,2H),2.43(dd,J＝13.1,5.0Hz,1H),2.21(s,2H),2.03(s,3H),1.47(d,J＝5.5Hz,2H),0.96(s,6H).LCMS(ESI)C 35 H 40 FN 4 O 4 + [M+H] + Calculated 599.30, measured 599.3.
Example 278: preparation of 3- (5- (4- (4 '-fluoro-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) piperazine-1-carbonyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05448)
The title compound (GT-05448) was prepared according to the procedure for synthesis scheme 6 and example 76 (white solid, 21mg, yield 54.18%). 1 H NMR(400MHz,DMSO-d6)δ11.03(s,1H),7.75(t,J＝21.3Hz,2H),7.49(d,J＝22.2Hz,1H),7.30(s,2H),7.14(s,2H),5.15(d,J＝13.2Hz,1H),4.46(dt,J＝27.6,17.3Hz,4H),4.03–3.73(m,1H),3.55(d,J＝12.6Hz,1H),3.22(dd,J＝37.7,20.5Hz,1H),3.03(d,J＝11.0Hz,1H),2.92(s,1H),2.61(d,J＝17.6Hz,3H),2.33(s,2H),2.14(s,1H),2.03(s,2H),1.73(s,2H),1.63(s,2H),1.51(d,J＝9.0Hz,1H).LCMS(ESI)C 31 H 32 FN 4 O 5 + [M+H] + Calculated 559.24, measured 559.3.
Example 279: preparation of 3- (5- (3- (4 '-fluoro-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) -3, 6-diazabicyclo [3.1.1] heptane-6-carbonyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05449)
Reference toSynthesis of scheme 6 and example 76 provide the title compound (GT-05449) (white solid, 19mg, yield 47.99%). 1 H NMR(400MHz,DMSO-d6)δ11.02(s,1H),7.76(d,J＝7.8Hz,1H),7.58(s,1H),7.45(d,J＝7.2Hz,1H),7.29(s,2H),7.18(d,J＝7.4Hz,2H),5.13(dd,J＝13.2,5.0Hz,1H),4.48(d,J＝17.6Hz,1H),4.35(d,J＝17.6Hz,1H),3.61(d,J＝68.7Hz,2H),3.18(d,J＝53.0Hz,4H),3.00–2.76(m,2H),2.60(d,J＝17.4Hz,2H),2.47–2.20(m,3H),2.02(dd,J＝19.2,13.6Hz,3H),1.71(s,4H).LCMS(ESI)C 32 H 32 FN 4 O 5 + [M+H] + Calculated 571.24, measured 571.2.
Example 280: preparation of 3- (5- (3- ((4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptane-6-carbonyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05450)
The title compound (GT-05450) (white solid, 14mg, yield 21.67%) was prepared according to the procedure of synthesis scheme 6 and example 76. 1 H NMR(400MHz,DMSO-d6)δ11.03(s,1H),10.81(s,1H),7.80(d,J＝7.8Hz,1H),7.60(s,1H),7.44(s,1H),7.20(d,J＝8.1Hz,3H),7.12(s,2H),5.16(dd,J＝13.1,4.7Hz,1H),4.70(s,1H),4.46(dd,J＝40.5,17.5Hz,3H),3.64(s,4H),2.99–2.84(m,2H),2.68(dd,J＝44.7,18.4Hz,4H),2.39–2.24(m,3H),2.05(s,3H),1.45(s,2H),0.95(s,6H).LCMS(ESI)C 34 H 38 FN 4 O 4 + [M+H] + Calculated 585.29, measured 585.3.
Example 281: preparation of 3- (5- (3- ((4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -3, 8-diazabicyclo [3.2.1] octane-8-carbonyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05451)
The title compound (GT-05451) was prepared according to the procedure of synthesis scheme 6 and example 76 (white solid, 14mg, yield 21.19%). 1 H NMR(400MHz,DMSO-d6)δ11.03(s,1H),7.84(d,J＝7.7Hz,1H),7.64(s,1H),7.52(d,J＝7.4Hz,1H),7.31–7.21(m,2H),7.16(s,3H),5.16(d,J＝9.1Hz,1H),4.56–4.42(m,2H),4.39(s,1H),3.63(d,J＝22.5Hz,3H),3.38–3.28(m,1H),3.20(s,1H),2.98–2.85(m,2H),2.72–2.57(m,3H),2.29(d,J＝30.2Hz,3H),2.10(s,2H),1.80(s,2H),1.47(s,3H),0.96(s,7H).LCMS(ESI)C 35 H 40 FN 4 O 4 + [M+H] + Calculated 599.30, measured 599.3.
Example 282: preparation of 3- (5- (5- ((4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -2, 5-diazabicyclo [2.2.1] heptane-2-carbonyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05452)
The title compound (GT-05452) was prepared according to the procedure for synthesis scheme 6 and example 76 (white solid, 18mg, yield 27.86%). 1 H NMR(400MHz,DMSO-d6)δ11.03(s,1H),7.86–7.82(m,1H),7.82(s,1H),7.72(s,1H),7.27(d,J＝8.3Hz,2H),7.21(s,1H),7.20–7.17(m,2H),5.19–5.13(m,1H),4.57–4.46(m,2H),4.44–4.37(m,2H),3.77–3.57(m,8H),2.95(dd,J＝30.1,11.9Hz,3H),2.63(t,J＝15.9Hz,2H),2.45–2.40(m,1H),2.18(d,J＝31.3Hz,4H),2.04(d,J＝9.1Hz,5H),1.50–1.43(m,3H),0.95(s,6H).LCMS(ESI)C 34 H 38 FN 4 O 4 + [M+H] + Calculated 585.29, measured 585.3.
Example 283: preparation of 3- (5- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -1, 4-diazepan-1-carbonyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05453)
The title compound (GT-05453) (white solid, 32mg, yield 48.11%) was prepared according to the procedure of synthesis scheme 6 and example 76. 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),8.87(s,1H),7.81(t,J＝9.2Hz,1H),7.59(d,J＝10.2Hz,1H),7.48(t,J＝8.9Hz,3H),7.14(dd,J＝13.8,8.1Hz,2H),5.20–5.07(m,1H),4.50(dd,J＝17.2,7.1Hz,1H),4.39(d,J＝6.2Hz,1H),3.73–3.55(m,4H),3.41(d,J＝35.9Hz,4H),3.07–2.86(m,3H),2.67–2.55(m,2H),2.41(d,J＝10.0Hz,1H),2.20(d,J＝19.6Hz,2H),2.05(d,J＝13.7Hz,4H),1.48(d,J＝17.0Hz,2H),0.96(s,6H).LCMS(ESI)C 34 H 40 ClN 4 O 4 + [M+H] + Calculated 603.27, measured 603.3.
Example 284: preparation of 5- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -1, 4-diazacycloheptane-1-carbonyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-05454)
The title compound (GT-05454) (white solid, 19mg, yield 29.36%) was prepared according to the procedure of synthesis scheme 6 and example 76. 1 H NMR(400MHz,DMSO-d6)δ11.15(s,1H),9.90(s,1H),8.01–7.96(m,1H),7.90–7.81(m,1H),7.52–7.36(m,2H),7.14(dd,J＝18.4,7.1Hz,2H),5.30–5.10(m,1H),3.80–3.53(m,4H),3.45(d,J＝39.5Hz,2H),3.24(d,J＝13.7Hz,1H),2.91(dd,J＝12.8,9.1Hz,3H),2.58(dd,J＝24.9,11.7Hz,2H),2.31(d,J＝19.1Hz,3H),2.07(d,J＝12.4Hz,3H),1.46(dd,J＝13.3,6.1Hz,2H),0.95(s,6H).LCMS(ESI)C 34 H 38 ClN 4 O 5 + [M+H] + Calculated 617.25, measured 617.3.
Example 285: preparation of 3- (5- (4- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) piperazine-1-carbonyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05455)
The title compound (GT-05455) (white solid, 28mg, yield 45.36%) was prepared according to the procedure of synthesis scheme 6 and example 76. 1 H NMR(400MHz,DMSO-d6)δ11.03(s,1H),10.94(s,1H),8.06(s,1H),7.79(d,J＝7.8Hz,1H),7.64(s,1H),7.54(dd,J＝13.0,7.9Hz,5H),7.39(d,J＝8.2Hz,2H),7.32(d,J＝6.0Hz,1H),5.14(dd,J＝13.3,5.1Hz,1H),4.43(dd,J＝50.0,17.6Hz,4H),4.26(s,1H),3.60(s,2H),3.24(d,J＝10.8Hz,3H),3.01–2.86(m,2H),2.79(s,1H),2.61(d,J＝16.8Hz,1H),2.41(tt,J＝13.2,6.5Hz,1H),2.00(dd,J＝15.4,10.3Hz,1H).LCMS(ESI)C 31 H 30 ClN 4 O 4 + [M+H] + Calculated 557.20, found 557.2.
Example 286: preparation of 5- (4- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) piperazine-1-carbonyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-05456)
The title compound (GT-05456) (white solid, 25mg, yield 41.57%) was prepared according to the procedure of synthesis scheme 6 and example 76. 1 H NMR(400MHz,DMSO-d6)δ11.16(s,1H),10.70(s,1H),8.00(d,J＝7.6Hz,1H),7.94(d,J＝7.7Hz,1H),7.90–7.84(m,1H),7.56(s,2H),7.53(s,1H),7.39(d,J＝8.3Hz,2H),7.33(d,J＝6.5Hz,1H),5.19(dd,J＝12.8,5.4Hz,1H),4.33(d,J＝64.6Hz,2H),3.54(s,2H),3.25(s,4H),3.02(s,1H),2.93–2.85(m,1H),2.77(s,1H),2.58(dd,J＝24.7,12.0Hz,2H),2.11–2.00(m,1H).LCMS(ESI)C 31 H 28 ClN 4 O 5 + [M+H] + Calculated 571.17, measured 571.1.
Example 287: preparation of 3- (5- (6- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptane-3-carbonyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05457)
The title compound (GT-05457) (white solid, 12mg, yield 18.10%) was prepared according to the procedure of synthesis scheme 6 and example 76. 1 H NMR(400MHz,DMSO-d6)δ11.09(s,1H),11.01(s,1H),7.85–7.80(m,1H),7.62(t,J＝9.2Hz,1H),7.48(d,J＝8.3Hz,1H),7.43(d,J＝6.6Hz,2H),7.22(d,J＝8.3Hz,2H),5.17–5.13(m,1H),4.54–4.46(m,2H),4.23(s,1H),4.12–3.97(m,3H),3.57(d,J＝16.6Hz,3H),2.92(dd,J＝21.7,9.0Hz,2H),2.44(dd,J＝17.9,8.4Hz,2H),2.21(d,J＝30.8Hz,4H),1.44(s,3H),0.96(s,6H).LCMS(ESI)C 34 H 38 ClN 4 O 4 + [M+H] + Calculated 601.26, found 601.3.
Example 288: preparation of 3- (5- (3- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -3, 8-diazabicyclo [3.2.1] octane-8-carbonyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05458)
The title compound (GT-05458) (white solid, 12mg, 17.71% yield) was prepared according to the procedure of synthesis scheme 6 and example 76. 1 H NMR(400MHz,DMSO-d6)δ11.02(s,1H),9.72(s,1H),7.79(d,J＝28.3Hz,1H),7.64(s,1H),7.50(dd,J＝14.6,7.3Hz,2H),7.38(s,1H),7.20–7.04(m,2H),5.15(d,J＝8.1Hz,1H),4.47(dd,J＝45.9,19.3Hz,2H),3.65(s,2H),3.40–3.31(m,1H),3.13(d,J＝4.9Hz,2H),2.96–2.78(m,2H),2.61(d,J＝17.2Hz,2H),2.31(dd,J＝56.0,39.7Hz,4H),2.03–1.70(m,6H),1.46(s,2H),0.95(s,6H).LCMS(ESI)C 35 H 40 ClN 4 O 4 + [M+H] + Calculated 615.27, measured 615.3.
Example 289: preparation of 3- (4-fluoro-5- ((4- ((4 '-fluoro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05602)
The title compound (GT-05602) (white solid, 40mg, yield 49.83%) was prepared according to the method of FIG. 1. 1 H NMR(400MHz,DMSO-d6)δ11.02(s,1H),7.86(s,1H),7.75(s,1H),7.64(d,J＝7.7Hz,1H),7.47(d,J＝4.4Hz,2H),7.40(dd,J＝8.4,5.6Hz,2H),7.29(t,J＝8.7Hz,3H),5.13(dd,J＝13.2,5.0Hz,1H),4.59–4.40(m,2H),4.22(s,3H),3.19(s,5H),2.98–2.83(m,2H),2.83–2.69(m,1H),2.61(d,J＝17.4Hz,1H),2.48–2.39(m,1H),2.07–1.95(m,1H).LCMS(ESI)C 31 H 31 F 2 N 4 O 3 + [M+H] + Calculated 545.24, measured 545.3.
Example 290: preparation of 3- (6-fluoro-5- ((4- ((4 '-fluoro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05603)
The title compound (GT-05603) was prepared according to the method of scheme 1 (white solid, 36mg, yield 44.84%). 1 H NMR(400MHz,DMSO-d6)δ11.02(s,1H),7.84(s,2H),7.62(d,J＝8.5Hz,1H),7.50–7.44(m,2H),7.40(dd,J＝8.5,5.6Hz,2H),7.30(d,J＝8.7Hz,3H),5.13(dd,J＝13.3,5.1Hz,1H),4.39(dd,J＝50.3,17.4Hz,3H),4.19(s,2H),3.18(s,5H),2.96–2.85(m,2H),2.80(s,1H),2.61(d,J＝16.4Hz,1H),2.45–2.35(m,1H),2.05–1.95(m,1H).LCMS(ESI)C 31 H 31 F 2 N 4 O 3 + [M+H] + Calculated 545.24, measured 545.3.
Example 291: preparation of 3- (7-fluoro-5- ((4- ((4 '-fluoro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05604)
The title compound (GT-05604) was prepared according to the procedure for synthesis scheme 1 (white solid, 29mg, yield 36.12%). 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),7.84(s,1H),7.57(s,1H),7.47(s,2H),7.41(dd,J＝8.5,5.6Hz,2H),7.29(t,J＝8.7Hz,3H),5.09(dd,J＝13.3,5.0Hz,1H),4.42(dd,J＝52.0,17.9Hz,3H),4.26(s,2H),3.14(s,5H),2.97–2.84(m,2H),2.81–2.69(m,1H),2.60(d,J＝17.6Hz,1H),2.43–2.32(m,1H),2.05–1.95(m,1H).LCMS(ESI)C 31 H 31 F 2 N 4 O 3 + [M+H] + Calculated 545.24, measured 545.3.
Example 292: preparation of 3- (4- ((4- ((4 '-fluoro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05605)
The title compound (GT-05605) was prepared according to the method of scheme 1 (white solid, 35mg, yield 44.91%). 1 H NMR(400MHz,DMSO-d6)δ11.04(s,1H),7.77(d,J＝6.7Hz,3H),7.58(t,J＝7.3Hz,1H),7.46(s,2H),7.41(dd,J＝8.4,5.6Hz,2H),7.29(t,J＝8.6Hz,3H),5.15(dd,J＝13.2,5.1Hz,1H),4.70(s,1H),4.43(d,J＝17.9Hz,1H),4.22(s,4H),3.15(s,5H),2.99–2.88(m,2H),2.86–2.73(m,1H),2.63(d,J＝16.9Hz,2H),2.39–2.25(m,1H),2.05–1.94(m,1H).LCMS(ESI)C 31 H 32 FN 4 O 3 + [M+H] + Calculated 527.25, measured 527.3.
Example 293: preparation of 3- (6- ((4- ((4 '-fluoro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05606)
The title compound (GT-05606) was prepared according to the method of scheme 1 (white solid, 30mg, yield 38.49%). 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),7.93(s,1H),7.80(d,J＝7.0Hz,1H),7.68(d,J＝7.7Hz,1H),7.45(s,1H),7.40(dd,J＝8.5,5.6Hz,2H),7.29(dd,J＝11.3,6.0Hz,3H),5.12(dd,J＝13.3,5.1Hz,1H),4.50(d,J＝17.7Hz,1H),4.37(d,J＝17.6Hz,2H),3.70(s,2H),3.51(s,2H),3.35–3.22(m,3H),3.15(s,3H),2.94–2.86(m,1H),2.63(t,J＝16.9Hz,2H),2.41(dt,J＝13.4,8.8Hz,1H),2.05–1.96(m,1H).LCMS(ESI)C 31 H 32 FN 4 O 3 + [M+H] + Calculated 527.25, measured 527.3.
Example 294: preparation of 3- (5- ((3- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-6-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05607)
The title compound (GT-05607) was prepared according to the method of scheme 1 (white solid, 14mg, yield 18.73%). 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),9.71(s,1H),7.81–7.77(m,1H),7.75–7.67(m,1H),7.63(s,1H),7.49(d,J＝8.3Hz,3H),7.40(s,2H),7.28(d,J＝6.5Hz,1H),5.13(dd,J＝13.3,5.0Hz,1H),4.66(d,J＝4.7Hz,1H),4.48(d,J＝17.5Hz,1H),4.35(d,J＝17.6Hz,1H),4.28(d,J＝9.9Hz,1H),4.15(s,1H),3.99(s,1H),3.55(s,2H),3.16(s,2H),2.95(dd,J＝36.7,24.4Hz,2H),2.67(s,1H),2.59(s,1H),2.50–2.46(m,1H),2.46–2.36(m,1H),2.33(s,1H),2.01(d,J＝5.8Hz,1H).LCMS(ESI)C 32 H 32 ClN 4 O 3 + [M+H] + Calculated 555.22, measured 555.3.
Example 295: preparation of 3- (5- ((3- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-6-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05608)
The title compound (GT-05608) was prepared according to the method of scheme 1 (white solid, 24mg, yield 31.22%). 1 H NMR(400MHz,DMSO-d6)δ11.05(s,1H),9.18(s,1H),7.84–7.73(m,1H),7.69(d,J＝7.7Hz,1H),7.62(dd,J＝16.2,6.8Hz,1H),7.51–7.46(m,3H),7.40(ddd,J＝10.5,6.0,2.7Hz,2H),7.26(dd,J＝11.6,5.5Hz,1H),5.19–5.09(m,1H),4.76–4.54(m,2H),4.46–4.37(m,1H),4.33(d,J＝7.1Hz,1H),4.20(d,J＝5.6Hz,1H),3.51(dd,J＝28.7,15.1Hz,4H),3.17(d,J＝10.0Hz,1H),2.99(s,1H),2.92(d,J＝13.6Hz,1H),2.61(d,J＝16.5Hz,2H),2.48–2.26(m,2H),2.06(dd,J＝33.7,28.5Hz,2H).LCMS(ESI)C 32 H 31 ClFN 4 O 3 + [M+H] + Calculated 573.21, measured 573.2.
Example 296: preparation of 3- (5- ((3- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-6-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05609)
The title compound (GT-05609) was prepared according to the method of scheme 1 (white solid, 38mg, yield 49.43%). 1 H NMR(400MHz,DMSO-d6)δ11.02(s,1H),9.13(s,1H),7.91–7.79(m,1H),7.67(t,J＝8.5Hz,1H),7.60(d,J＝8.6Hz,1H),7.52–7.45(m,3H),7.43–7.36(m,2H),7.26(dd,J＝11.4,5.3Hz,1H),5.19–5.05(m,1H),4.68(d,J＝21.2Hz,1H),4.47(dd,J＝17.2,4.7Hz,1H),4.40–4.26(m,2H),4.22(d,J＝5.8Hz,1H),3.72(s,1H),3.52(d,J＝44.4Hz,2H),2.94(dd,J＝31.5,14.7Hz,3H),2.61(d,J＝17.4Hz,3H),2.39(dd,J＝28.5,15.5Hz,2H),2.07(t,J＝29.8Hz,2H).LCMS(ESI)C 32 H 31 ClFN 4 O 3 + [M+H] + Calculated 573.21, measured 573.3.
Example 297: preparation of 3- (5- ((3- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-6-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05610)
The title compound (GT-05610) was prepared according to the method of scheme 1 (white solid, 26mg, yield 33.82%). 1 H NMR(400MHz,DMSO-d6)δ11.02(s,1H),7.58(s,1H),7.54(d,J＝10.0Hz,1H),7.52–7.45(m,4H),7.44–7.36(m,3H),7.27(d,J＝8.5Hz,1H),5.10(d,J＝12.9Hz,1H),4.65(s,1H),4.51(d,J＝18.4Hz,1H),4.37(d,J＝18.2Hz,1H),4.29(d,J＝18.1Hz,1H),4.15(s,1H),3.75(s,1H),3.48(s,2H),3.13(d,J＝13.2Hz,1H),3.04–2.87(m,3H),2.68–2.57(m,2H),2.41(d,J＝13.5Hz,1H),2.33(s,1H),2.16(s,1H),2.02(s,1H).LCMS(ESI)C 32 H 31 ClFN 4 O 3 + [M+H] + Calculated 573.21, measured 573.2.
Example 298: preparation of 3- (5- ((4- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) -1, 4-diazepan-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05611)
The title compound (GT-05611) was prepared according to the method of scheme 1 (white solid, 39mg, yield 46.54%). 1 H NMR(400MHz,DMSO-d6)δ11.62(d,J＝56.5Hz,1H),11.03(s,1H),8.07(d,J＝35.1Hz,1H),7.87–7.76(m,2H),7.70(d,J＝35.4Hz,1H),7.53(d,J＝10.5Hz,4H),7.44–7.34(m,2H),7.34–7.24(m,1H),5.14(dd,J＝13.1,4.7Hz,1H),4.47(t,J＝15.8Hz,2H),4.36(d,J＝17.3Hz,3H),3.79(s,1H),3.54(s,2H),3.31(s,2H),3.06(s,1H),3.01–2.74(m,2H),2.61(d,J＝16.3Hz,1H),2.48–2.35(m,1H),2.03(dd,J＝29.9,24.3Hz,3H).LCMS(ESI)C 32 H 34 ClN 4 O 3 + [M+H] + Calculated 557.23, measured 557.3.
Example 299: preparation of 3- (5- ((7- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05612)
The title compound (GT-05612) was prepared according to the method of scheme 1 (white solid, 23mg, yield 31.87%). 1 H NMR(400MHz,DMSO-d6)δ11.54(s,1H),11.01(s,1H),10.38(s,1H),8.14–8.05(m,1H),7.82–7.74(m,2H),7.69(t,J＝7.0Hz,1H),7.55–7.46(m,4H),7.37(t,J＝8.8Hz,2H),7.32–7.25(m,1H),5.13(dd,J＝13.1,4.8Hz,1H),4.55–4.41(m,3H),4.33(dd,J＝17.7,3.8Hz,1H),4.20(s,2H),3.90(d,J＝6.4Hz,1H),3.81(s,2H),3.71(d,J＝5.3Hz,1H),3.16(dd,J＝24.7,12.1Hz,2H),2.91(dd,J＝22.0,9.1Hz,1H),2.72(s,1H),2.61(d,J＝16.3Hz,2H),2.47–2.37(m,1H),2.31(d,J＝12.8Hz,1H),2.04(dd,J＝24.3,10.8Hz,4H).LCMS(ESI)C 34 H 36 ClN 4 O 3 + [M+H] + Calculated 583.25, measured 583.2.
Example 300: preparation of 3- (5- ((5- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05613)
The title compound (GT-05613) was prepared according to the method of scheme 1 (white solid, 34mg, yield 46.45%). 1 H NMR(400MHz,DMSO-d6)δ10.96(d,J＝42.9Hz,2H),7.89(s,1H),7.84–7.78(m,1H),7.69(dd,J＝42.0,12.0Hz,2H),7.52(dd,J＝18.0,7.0Hz,4H),7.38(d,J＝8.2Hz,2H),7.32(s,1H),5.13(dd,J＝13.2,5.0Hz,1H),4.52–4.29(m,6H),3.68(s,1H),3.49(s,4H),3.21(s,2H),3.04(s,2H),2.98–2.84(m,2H),2.61(d,J＝16.7Hz,1H),2.42(d,J＝12.9Hz,1H),2.05–1.96(m,1H).LCMS(ESI)C 33 H 34 ClN 4 O 3 + [M+H] + Calculated 569.23, measured 569.2.
Example 301: preparation of 3- (5- (4- ((4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazine-1-carbonyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05614)
The title compound (GT-05614) (white solid, 12mg, 14.92% yield) was prepared according to the procedure of synthesis scheme 6 and example 76. 1 H NMR(400MHz,DMSO-d6)δ11.03(s,1H),7.80(d,J＝7.8Hz,1H),7.65(s,1H),7.54(d,J＝7.7Hz,1H),7.23(t,J＝8.7Hz,2H),7.15(t,J＝6.8Hz,2H),5.14(dd,J＝13.3,5.1Hz,1H),4.49(d,J＝17.7Hz,2H),4.37(d,J＝17.6Hz,1H),3.62(s,6H),3.28–3.16(m,2H),2.97–2.82(m,2H),2.66(dd,J＝36.4,20.5Hz,2H),2.47–2.34(m,1H),2.25(d,J＝21.3Hz,2H),2.10–1.96(m,3H),1.48(s,2H),0.97(s,6H).LCMS(ESI)C 33 H 38 FN 4 O 4 + [M+H] + Calculated 573.29, measured 573.3.
Example 302: preparation of 2- (2, 6-dioxopiperidin-3-yl) -5- (4- ((4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazine-1-carbonyl) isoindoline-1, 3-dione (GT-05615)
The title compound (GT-05615) (white solid, 8.6mg, yield 10.46%) was prepared according to the procedure of synthesis scheme 6 and example 76. 1 H NMR(400MHz,DMSO-d6)δ11.15(s,1H),9.26(s,1H),8.01(d,J＝7.6Hz,1H),7.96(s,1H),7.88(d,J＝8.0Hz,1H),7.24(t,J＝8.5Hz,2H),7.16(d,J＝5.4Hz,2H),5.19(dd,J＝12.9,5.5Hz,1H),4.48(s,1H),3.49(s,4H),3.23–3.15(m,2H),2.95–2.84(m,2H),2.68–2.57(m,2H),2.55(d,J＝4.9Hz,2H),2.21(s,2H),2.06(d,J＝8.5Hz,3H),1.48(s,2H),0.97(s,6H).LCMS(ESI)C 33 H 36 FN 4 O 5 + [M+H] + Calculated 587.27, measured 587.3.
Example 303: preparation of 3- (5- (4- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) -1, 4-diazepan-1-carbonyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05616)
The title compound (GT-05616) (white solid, 36mg, yield 42.63%) was prepared according to the procedure of synthesis scheme 6 and example 76. 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),9.79(s,1H),8.00–7.83(m,1H),7.79(t,J＝7.4Hz,1H),7.62–7.56(m,3H),7.55–7.48(m,2H),7.43–7.37(m,2H),7.35(d,J＝7.9Hz,1H),5.13(dd,J＝13.2,5.2Hz,1H),4.55–4.27(m,4H),3.62–3.50(m,2H),3.44(s,2H),3.24(s,2H),3.03(t,J＝26.1Hz,2H),2.61(d,J＝16.1Hz,1H),2.47–2.36(m,1H),2.05(d,J＝17.4Hz,2H).LCMS(ESI)C 32 H 32 ClN 4 O 4 + [M+H] + Calculated 571.21, found 571.3.
Example 304: preparation of 3- (5- (7- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) -2, 7-diazaspiro [3.5] nonane-2-carbonyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05641)
The title compound (GT-05641) (white solid, 33mg, yield 37.47%) was prepared according to the procedure of synthesis scheme 6 and example 76. 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),9.13(s,1H),7.83(s,1H),7.78(d,J＝7.8Hz,2H),7.71(t,J＝6.7Hz,1H),7.59–7.49(m,4H),7.39(d,J＝8.3Hz,1H),7.36–7.29(m,2H),5.13(d,J＝13.1Hz,1H),4.48(dd,J＝17.7,4.9Hz,1H),4.36(t,J＝8.6Hz,1H),4.28(d,J＝9.1Hz,2H),4.00(d,J＝8.1Hz,1H),3.96(d,J＝7.1Hz,1H),3.76(s,2H),3.16(s,2H),2.98–2.89(m,1H),2.78(d,J＝40.7Hz,2H),2.65(dd,J＝32.5,17.3Hz,2H),2.41(d,J＝13.3Hz,1H),1.99(d,J＝11.8Hz,2H),1.84(d,J＝14.5Hz,2H).LCMS(ESI)C 34 H 34 ClN 4 O 4 + [M+H] + Calculated 597.23, measured 597.3.
Example 305: preparation of 3- (5- (5- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) octahydropyrrolo [3,4-c ] pyrrole-2-carbonyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05642)
The title compound (GT-05642) (white solid, 39mg, yield 45.29%) was prepared according to the procedure of synthesis scheme 6 and example 76. 1 H NMR(400MHz,DMSO-d6)δ11.02(s,1H),10.14(d,J＝72.4Hz,1H),7.88–7.80(m,1H),7.76(d,J＝9.8Hz,1H),7.65(d,J＝24.8Hz,1H),7.54(t,J＝9.1Hz,5H),7.39(d,J＝8.2Hz,2H),7.34(d,J＝7.9Hz,1H),5.15(dd,J＝13.3,4.9Hz,1H),4.50(t,J＝14.0Hz,1H),4.42–4.37(m,2H),3.72(d,J＝47.6Hz,2H),3.49(s,3H),3.28–3.14(m,2H),3.01–2.89(m,3H),2.82(d,J＝14.5Hz,1H),2.62(d,J＝16.2Hz,2H),2.42(dd,J＝17.5,8.8Hz,1H),2.02(d,J＝5.3Hz,1H).LCMS(ESI)C 33 H 32 ClN 4 O 4 + [M+H] + Calculated 583.21, measured 583.2.
Example 306: preparation of 3- (5- (3- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptane-6-carbonyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05643)
The title compound (GT-05643) (white solid, 25mg, yield 29.70%) was prepared according to the procedure of synthesis scheme 6 and example 76. 1 H NMR(400MHz,DMSO-d6)δ11.89(s,1H),11.03(s,1H),8.05(s,1H),7.79(d,J＝7.8Hz,1H),7.56(s,2H),7.55(s,3H),7.34(s,1H),7.31(s,2H),5.16(dd,J＝13.2,4.6Hz,1H),4.62(s,1H),4.50(t,J＝20.1Hz,2H),4.38(d,J＝18.7Hz,2H),4.25(s,1H),3.37–3.26(m,3H),2.97–2.86(m,1H),2.71(s,1H),2.63(d,J＝17.6Hz,2H),2.45(s,1H),2.38(s,1H),2.08–1.98(m,1H).LCMS(ESI)C 32 H 30 ClN 4 O 4 + [M+H] + Calculated 569.20, measured 569.3.
Example 307: preparation of 3- (5- ((4- (4 '-chloro- [1,1' -biphenyl ] -2-carbonyl) -1, 4-diazepan-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05644)
The title compound (GT-05644) was prepared according to the method of scheme 1 (white solid, 45mg, yield 57.87%). 1 H NMR(400MHz,DMSO)δ11.01(s,1H),10.72(s,1H),7.84(s,1H),7.77(d,J＝14.2Hz,1H),7.61(s,1H),7.54(dd,J＝16.7,9.4Hz,3H),7.49–7.33(m,4H),5.15(dd,J＝13.3,5.0Hz,1H),4.52(d,J＝17.8Hz,1H),4.40(d,J＝17.2Hz,2H),4.18(d,J＝42.9Hz,1H),3.41(s,2H),3.34–3.28(m,3H),3.21(s,2H),3.06(s,1H),2.96–2.87(m,1H),2.79(s,1H),2.61(d,J＝17.7Hz,1H),2.43(d,J＝9.6Hz,1H),2.14–1.93(m,2H),1.80(s,1H).LCMS(ESI)C 32 H 32 ClN 4 O 4 + [M+H] + Calculated 571.21, measured 571.2.
Example 308: preparation of 3- (5- ((5- (4 '-chloro- [1,1' -biphenyl ] -2-carbonyl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) methyl) -1-oxo-isoindolin-2-yl) piperidine-2, 6-dione (GT-05645)
The title compound (GT-05645) was prepared according to the method of scheme 1 (white solid, 47mg, yield 59.27%). 1 H NMR(400MHz,DMSO-d6)δ11.07(d,J＝43.1Hz,2H),7.81(t,J＝7.0Hz,2H),7.70(d,J＝8.0Hz,1H),7.60–7.55(m,2H),7.49(d,J＝6.4Hz,3H),7.47–7.41(m,3H),5.14(dd,J＝13.2,3.8Hz,1H),4.50(d,J＝17.6Hz,1H),4.47–4.35(m,3H),3.66–3.54(m,2H),3.33–3.20(m,3H),2.99–2.83(m,4H),2.75(s,1H),2.63(t,J＝16.6Hz,2H),2.46–2.38(m,1H),2.04–1.99(m,1H).LCMS(ESI)C 33 H 32 ClN 4 O 4 + [M+H] + Calculated 583.21, measured 583.2.
Example 309: preparation of 3- (1-oxo-5- ((4- (2- (thiophen-2-yl) benzyl) piperazin-1-yl) methyl) isoindolin-2-yl) piperidine-2, 6-dione (GT-05519)
The title compound (GT-05519) was prepared according to the method of scheme 1 (white solid, 30mg, 39.89% yield). 1 H NMR(400MHz,DMSO)δ11.01(s,1H),7.80(d,J＝7.6Hz,2H),7.71–7.64(m,2H),7.45(s,3H),7.26(d,J＝2.8Hz,1H),7.17(dd,J＝5.0,3.6Hz,1H),5.13(dd,J＝13.3,5.0Hz,1H),4.39(t,J＝25.6Hz,4H),3.36–3.26(m,3H),3.16(s,4H),2.98–2.85(m,2H),2.61(d,J＝16.4Hz,1H),2.47–2.37(m,1H),2.04–1.96(m,1H).LCMS(ESI)C 29 H 31 N 4 O 3 S + [M+H] + Calculated 515.21, measured 515.3.
Example 310: preparation of 3- (5- (4- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) amino) piperidine-1-carbonyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05646)
The title compound (GT-05646) (white solid, 30mg, 43.88% yield) was prepared according to the procedure of synthesis scheme 6 and example 76. 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),7.77(d,J＝7.8Hz,1H),7.60(s,1H),7.50(dd,J＝12.2,5.5Hz,3H),7.45–7.37(m,2H),7.21–7.14(m,1H),6.99(dd,J＝7.5,1.5Hz,1H),6.84(d,J＝8.2Hz,1H),6.70(t,J＝7.3Hz,1H),5.13(dd,J＝13.3,5.1Hz,1H),4.49(d,J＝17.7Hz,1H),4.36(d,J＝17.5Hz,2H),3.59(d,J＝10.1Hz,2H),3.15(s,1H),2.97(d,J＝11.6Hz,1H),2.95–2.86(m,1H),2.60(d,J＝17.8Hz,1H),2.46–2.32(m,1H),2.06–1.92(m,2H),1.79(s,1H),1.36(dd,J＝20.5,9.8Hz,2H).LCMS(ESI)C 31 H 30 ClN 4 O 4 + [M+H] + Calculated 557.20, found 557.2.
Example 311: preparation of 5- (4- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) amino) piperidine-1-carbonyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-05647)
The title compound (GT-05647) (white solid, 35mg, yield 49.83%) was prepared according to the procedure of synthesis scheme 6 and example 76. 1 H NMR(400MHz,DMSO-d6)δ11.14(s,1H),7.98(d,J＝7.6Hz,1H),7.90–7.82(m,2H),7.52(d,J＝8.4Hz,2H),7.42(d,J＝8.4Hz,2H),7.22–7.16(m,1H),6.99(dd,J＝7.5,1.4Hz,1H),6.85(d,J＝8.2Hz,1H),6.70(t,J＝7.4Hz,1H),5.18(dd,J＝12.7,5.4Hz,1H),4.36(d,J＝10.2Hz,1H),3.61(s,2H),3.18(s,1H),3.00(s,1H),2.93–2.85(m,1H),2.64–2.54(m,2H),2.10–2.02(m,1H),1.97(s,1H),1.78(s,1H),1.40(dd,J＝20.6,10.1Hz,2H).LCMS(ESI)C 31 H 28 ClN 4 O 5 + [M+H] + Calculated 571.17, measured 571.2.
Example 312: preparation of 3- (5- ((4- (4 '-chloro- [1,1' -biphenyl ] -2-carbonyl) piperazin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05649)
The title compound (GT-05649) was prepared according to the method of scheme 1 (white solid, 34mg, 47.52% yield). 1 H NMR(400MHz,DMSO-d6)δ11.03(s,1H),7.80(s,1H),7.67(d,J＝7.7Hz,1H),7.56(dd,J＝13.1,5.6Hz,1H),7.50(t,J＝8.0Hz,4H),7.46(s,1H),7.42–7.32(m,2H),5.14(dd,J＝13.2,5.1Hz,1H),4.58(d,J＝17.5Hz,1H),4.42(dd,J＝17.3,10.0Hz,3H),3.39(s,3H),3.34–3.24(m,2H),3.14(s,2H),2.97–2.89(m,1H),2.79(s,1H),2.61(d,J＝17.4Hz,1H),2.49–2.37(m,1H),2.05–1.95(m,1H).LCMS(ESI)C 31 H 29 ClFN 4 O 4 + [M+H] + Calculated 575.19, measured 575.2.
Example 313: preparation of 3- (5- ((4- (4 '-chloro- [1,1' -biphenyl ] -2-carbonyl) piperazin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05650)
The title compound (GT-05650) was prepared according to the method of scheme 1 (white solid, 31mg, yield 43.33%). 1 H NMR(400MHz,DMSO-d6)δ11.02(s,1H),7.89(s,1H),7.65(d,J＝8.1Hz,1H),7.59–7.54(m,1H),7.50(t,J＝8.3Hz,4H),7.46(s,1H),7.38(s,2H),5.14(dd,J＝13.2,5.0Hz,1H),4.41(dd,J＝50.2,17.4Hz,4H),3.34–3.20(m,3H),3.17(s,2H),2.99–2.84(m,2H),2.83–2.68(m,1H),2.61(d,J＝17.5Hz,1H),2.41(tt,J＝28.2,14.0Hz,2H),2.05–1.98(m,1H).LCMS(ESI)C 31 H 29 ClFN 4 O 4 + [M+H] + Calculated 575.19, measured 575.2.
Example 314: preparation of 5- (6- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptane-3-carbonyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-05651)
The title compound (GT-05651) (white solid, 9.5mg, yield 11.05%) was prepared according to the procedure of synthesis scheme 6 and example 76. 1 H NMR(400MHz,DMSO-d6)δ11.15(s,1H),8.09–8.01(m,1H),7.93(d,J＝18.1Hz,1H),7.48(d,J＝7.8Hz,1H),7.41(d,J＝7.6Hz,1H),7.21(d,J＝7.4Hz,2H),5.20(dd,J＝12.7,5.3Hz,1H),4.60(s,1H),4.12(t,J＝42.1Hz,2H),3.78(d,J＝37.6Hz,1H),3.55(s,3H),3.27–3.12(m,1H),3.10–2.81(m,2H),2.70–2.53(m,2H),2.25(d,J＝63.2Hz,3H),2.12–1.82(m,4H),1.44(s,2H),0.97(s,6H).LCMS(ESI)C 34 H 36 ClN 4 O 5 + [M+H] + Calculated 615.24, measured 615.3.
Example 315: preparation of 5- (3- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -3, 8-diazabicyclo [3.2.1] octane-8-carbonyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-05652)
The title compound (GT-05652) (white solid, 40mg, yield 45.53%) was prepared according to the procedure of synthesis scheme 6 and example 76. 1 H NMR(400MHz,DMSO-d6)δ11.16(s,1H),9.80(s,1H),8.03(s,1H),7.88(dd,J＝11.1,3.5Hz,2H),7.46(d,J＝46.7Hz,2H),7.13(s,2H),5.20(s,1H),4.06(s,1H),3.64(s,2H),3.23–2.97(m,2H),2.92(dd,J＝22.3,8.8Hz,2H),2.68–2.52(m,3H),2.28(s,2H),2.00(s,4H),1.76–1.67(m,1H),1.61(dd,J＝9.2,4.2Hz,1H),1.45(s,2H),1.31–1.13(m,2H),1.06(dd,J＝16.2,6.8Hz,1H),0.95(s,6H).LCMS(ESI)C 35 H 38 ClN 4 O 5 + [M+H] + Calculated 629.25, measured 629.3.
Example 316: preparation of 3- (5- ((4- (4 '-chloro- [1,1' -biphenyl ] -2-carbonyl) piperazin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05700)
The title compound (GT-05700) was prepared according to the method of scheme 1 (white solid, 30mg, yield 41.93%). 1 H NMR(400MHz,DMSO-d6)δ11.02(s,1H),7.54(dt,J＝19.2,9.0Hz,6H),7.45(d,J＝9.6Hz,2H),7.37(s,2H),5.10(dd,J＝13.2,5.0Hz,1H),4.44(dd,J＝50.5,17.8Hz,4H),4.32–3.96(m,1H),3.32–3.20(m,2H),3.06(s,2H),2.97–2.84(m,2H),2.83–2.70(m,1H),2.63(t,J＝18.1Hz,2H),2.43–2.32(m,1H),2.03–1.95(m,1H).LCMS(ESI)C 31 H 29 ClFN 4 O 4 + [M+H] + Calculated 575.19, measured 575.2.
Example 317: preparation of 3- (4- ((4- (4 '-chloro- [1,1' -biphenyl ] -2-carbonyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05701)
The title compound (GT-05701) was prepared according to the method of scheme 1 (white solid, 40mg, yield 57.60%). 1 H NMR(400MHz,DMSO-d6)δ11.06(s,1H),7.80(s,2H),7.63–7.50(m,5H),7.48(d,J＝7.5Hz,2H),7.41(dd,J＝21.1,12.6Hz,3H),5.17(d,J＝8.4Hz,1H),4.71(s,1H),4.45(d,J＝17.5Hz,2H),4.34(s,1H),3.34–3.28(m,2H),3.12(s,2H),3.01–2.85(m,2H),2.81(s,1H),2.65(d,J＝17.9Hz,1H),2.33(s,1H),2.05(s,1H).LCMS(ESI)C 31 H 30 ClN 4 O 4 + [M+H] + Calculated 557.20, measured 557.3.
Example 318: preparation of 3- (5- ((4- (2- (1-methyl-1H-pyrazol-5-yl) benzyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05702)
The title compound (GT-05702) was prepared according to the method of scheme 1 (white solid, 40mg, yield 53.37%). 1 H NMR(400MHz,DMSO-d6)δ11.02(d,J＝8.7Hz,1H),8.03(d,J＝13.5Hz,1H),7.87(s,1H),7.80(d,J＝7.8Hz,1H),7.74(d,J＝8.1Hz,1H),7.62–7.50(m,3H),7.45–7.35(m,1H),6.41(d,J＝1.4Hz,1H),5.13(dd,J＝13.3,5.1Hz,1H),4.48(d,J＝17.3Hz,3H),4.12(s,2H),3.61(s,3H),3.44(s,4H),3.30(s,3H),2.97–2.87(m,1H),2.61(d,J＝16.2Hz,1H),2.43(dt,J＝13.2,8.8Hz,1H),2.06–1.93(m,1H).LCMS(ESI)C 29 H 33 N 6 O 3 + [M+H] + Calculated 513.26, found 513.3.
Example 319: preparation of 3- (5- ((4- ((4- (4-chlorophenyl) pyridin-3-yl) methyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05703)
The title compound (GT-05703) was prepared according to the method of scheme 1 (white solid, 24mg, yield 30.39%). 1 H NMR(400MHz,DMSO)δ11.01(s,1H),8.95(s,1H),8.85(d,J＝5.7Hz,1H),7.87–7.79(m,3H),7.73(d,J＝8.1Hz,1H),7.61(q,J＝8.7Hz,4H),5.14(dd,J＝13.2,5.1Hz,1H),4.40(dd,J＝30.3,21.6Hz,4H),3.26(s,3H),3.07(s,3H),2.94–2.82(m,3H),2.61(d,J＝16.0Hz,3H),2.46–2.37(m,1H),2.06–1.97(m,1H).LCMS(ESI)C 30 H 31 ClN 5 O 3 + [M+H] + Calculated 544.21, measured 544.2.
Example 320: preparation of 3- (5- ((6- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05704)
The title compound (GT-05704) was prepared according to the method of scheme 1 (white solid, 30mg, yield 37.32%). 1 H NMR(400MHz,DMSO-d6)δ10.99(s,1H),9.41(s,1H),7.88(d,J＝6.7Hz,1H),7.72(d,J＝7.7Hz,1H),7.58(d,J＝8.4Hz,1H),7.54–7.41(m,5H),7.39(d,J＝8.4Hz,1H),7.33(t,J＝8.7Hz,1H),5.19–5.06(m,1H),4.54(s,1H),4.46(d,J＝17.4Hz,1H),4.33(d,J＝17.4Hz,1H),4.12(d,J＝14.5Hz,2H),3.66(s,1H),3.44(s,2H),3.03–2.77(m,2H),2.76–2.53(m,4H),2.41(d,J＝13.1Hz,2H),2.01(d,J＝12.0Hz,2H).LCMS(ESI)C 32 H 32 ClN 4 O 3 + [M+H] + Calculated 555.22, measured 555.2.
Example 321: preparation of 3- (5- (6- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptane-3-carbonyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05705)
The title compound (GT-05705) was prepared according to the procedure for synthesis scheme 6 and example 76 (white solid, 32mg, yield 38.02%). 1 H NMR(400MHz,DMSO-d6)δ11.02(s,1H),7.82(t,J＝8.3Hz,1H),7.71–7.62(m,1H),7.59–7.55(m,2H),7.52(s,3H),7.43(d,J＝8.3Hz,2H),7.34(s,1H),5.20–5.10(m,1H),4.61–4.45(m,2H),4.38(dd,J＝17.0,9.1Hz,1H),4.25(s,1H),4.14–3.83(m,2H),3.64–3.45(m,2H),3.27–3.07(m,1H),3.03–2.78(m,2H),2.62(d,J＝17.3Hz,2H),2.47–2.36(m,1H),2.13–1.76(m,2H).LCMS(ESI)C 32 H 30 ClN 4 O 4 + [M+H] + Calculated 569.20, measured 569.2.
Example 322: preparation of 3- (5- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -2- (trifluoromethyl) piperazine-1-carbonyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05706)
The title compound (GT-05706) was prepared according to the procedure for synthesis scheme 6 and example 76 (white solid, 3.3mg, yield 19.82%). 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),7.80(d,J＝7.6Hz,1H),7.62(d,J＝15.4Hz,1H),7.49(d,J＝7.4Hz,1H),7.38(d,J＝8.0Hz,2H),7.09(d,J＝8.3Hz,2H),5.13(dd,J＝13.3,5.1Hz,1H),4.54–4.44(m,1H),4.37(dd,J＝17.5,7.4Hz,1H),3.18–3.02(m,2H),2.90(dd,J＝21.8,9.6Hz,2H),2.60(d,J＝16.5Hz,2H),2.47–2.26(m,2H),2.24–2.07(m,2H),1.99(s,3H),1.41(s,2H),1.27–1.20(m,3H),0.95(s,6H).LCMS(ESI)C 34 H 37 ClF 3 N 4 O 4 + [M+H] + Calculated 657.24, measured 657.3.
Example 323: preparation of 3- (5- ((5- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05707)
The title compound (GT-05707) was prepared according to the method of FIG. 1 (white solid, 39mg, yield 48.52%). 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),7.88(s,2H),7.78(s,2H),7.50(s,4H),7.42(d,J＝8.1Hz,2H),7.31(s,1H),5.13(dd,J＝13.3,5.1Hz,1H),4.49(d,J＝17.7Hz,3H),4.36(d,J＝16.9Hz,2H),4.28–4.17(m,1H),4.02(s,3H),3.44(s,2H),3.35–3.25(m,2H),2.98–2.87(m,1H),2.61(d,J＝17.3Hz,2H),2.48–2.35(m,1H),2.05–1.97(m,1H).LCMS(ESI)C 32 H 32 ClN 4 O 3 + [M+H] + Calculated 555.22, measured 555.2.
Example 324: preparation of 3- (5- ((6- (4 '-chloro- [1,1' -biphenyl ] -2-carbonyl) -2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05708)
The title compound (GT-05708) was prepared according to the method of scheme 1 (white solid, 31mg, 40.00% yield). 1 H NMR(400MHz,DMSO-d6)δ11.27(s,1H),11.01(s,1H),7.78(d,J＝7.7Hz,1H),7.68(s,1H),7.62–7.51(m,2H),7.51–7.38(m,6H),5.13(dd,J＝13.3,5.0Hz,1H),4.48(d,J＝17.6Hz,1H),4.35(d,J＝17.6Hz,2H),4.20(s,1H),4.08–3.82(m,4H),3.80–3.54(m,2H),3.36(s,1H),3.13(s,1H),2.99–2.84(m,1H),2.61(d,J＝16.3Hz,1H),2.47–2.32(m,1H),2.09–1.95(m,1H).LCMS(ESI)C 32 H 30 ClN 4 O4 + [M+H] + Calculated 569.20, measured 569.2.
Example 325: preparation of 3- (5- ((6- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) -2, 6-diazaspiro [3.3] heptane-2-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05709)
The title compound (GT-05709) was prepared according to the method of scheme 1 (white solid, 8mg, yield 9.95%). 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),7.81(s,1H),7.65(s,1H),7.53(d,J＝11.7Hz,6H),7.39(d,J＝7.9Hz,3H),7.35–7.31(m,1H),5.22–5.07(m,1H),4.35(s,4H),4.16(s,4H),2.98–2.91(m,2H),2.67(s,3H),2.33(s,4H),2.01(s,1H).LCMS(ESI)C 32 H 32 ClN 4 O 3 + [M+H] + Calculated 555.22, measured 555.2.
Example 326: preparation of 3- (5- ((3- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) -3, 8-diazabicyclo [3.2.1] oct-8-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05710)
Preparation of the objects by reference to the method of scheme 1The title compound (GT-05710) (white solid, 35mg, yield 42.59%). 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),10.30(s,1H),7.89(s,1H),7.79(q,J＝8.0Hz,2H),7.50(d,J＝8.5Hz,2H),7.43(d,J＝8.5Hz,3H),7.37(dd,J＝5.5,3.5Hz,2H),7.25(dd,J＝8.3,4.8Hz,1H),5.13(dd,J＝13.2,5.1Hz,1H),4.42(dd,J＝50.7,17.6Hz,2H),4.24(d,J＝5.8Hz,2H),3.72(s,2H),3.49(s,3H),2.98–2.86(m,1H),2.61(d,J＝14.3Hz,3H),2.48–2.34(m,2H),2.14(d,J＝9.5Hz,2H),2.06–1.94(m,1H),1.67(s,2H).LCMS(ESI)C 33 H 34 ClN 4 O 3 + [M+H] + Calculated 569.23, measured 569.3.
Example 327: preparation of 3- (5- ((4- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) -2- (trifluoromethyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05711)
The title compound (GT-05711) was prepared according to the method of scheme 1 (white solid, 21mg, 71.96% yield). 1 H NMR(400MHz,DMSO-d6)δ10.99(s,1H),7.69(d,J＝7.8Hz,1H),7.51(d,J＝13.6Hz,4H),7.44(d,J＝7.4Hz,5H),7.29(s,1H),5.10(dd,J＝13.3,5.1Hz,1H),4.43(d,J＝17.4Hz,1H),4.33–4.24(m,1H),3.98(s,2H),3.46(s,2H),3.06–2.84(m,3H),2.82–2.70(m,1H),2.62(t,J＝18.5Hz,3H),2.39(ddd,J＝26.9,13.5,4.7Hz,2H),2.03–1.96(m,1H).LCMS(ESI)C 32 H 31 ClF 3 N 4 O 3 + [M+H] + Calculated 611.20, measured 611.3.
Example 328: preparation of 3- (5- ((3- (4 '-chloro- [1,1' -biphenyl ] -2-carbonyl) -3, 8-diazabicyclo [3.2.1] oct-8-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05788)
The title compound (GT-05788) was prepared according to the method of scheme 1 (white solid, 47mg, yield 59.27%). 1 H NMR(400MHz,DMSO)δ11.00(s,1H),7.79(t,J＝37.4Hz,3H),7.63–7.36(m,7H),7.34(d,J＝8.1Hz,1H),5.13(dd,J＝12.9,4.6Hz,1H),4.35(dt,J＝44.9,17.1Hz,5H),3.88(d,J＝22.5Hz,1H),3.62(d,J＝51.3Hz,3H),3.12–2.83(m,3H),2.61(d,J＝16.8Hz,1H),2.38(dd,J＝31.9,18.4Hz,2H),1.97(dd,J＝29.5,23.3Hz,2H),1.24(ddd,J＝49.0,24.2,19.6Hz,1H).LCMS(ESI)C 33 H 32 ClN 4 O 4 + [M+H] + Calculated 583.21, measured 583.2.
Example 329: preparation of 3- (5- ((4- (4 '-chloro- [1,1' -biphenyl ] -2-carbonyl) -2- (trifluoromethyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05789)
The title compound (GT-05789) was prepared according to the method of scheme 1 (white solid, 20mg, yield 7.85%). 1 H NMR(400MHz,DMSO)δ10.98(s,1H),7.66(d,J＝7.7Hz,1H),7.55(d,J＝8.4Hz,2H),7.49(d,J＝14.3Hz,3H),7.42(d,J＝8.3Hz,3H),7.40–7.28(m,2H),5.16–5.04(m,1H),4.35(dd,J＝52.7,17.2Hz,3H),4.08–3.84(m,2H),3.67(s,1H),3.27(s,1H),3.10(s,1H),2.91(t,J＝12.8Hz,1H),2.82–2.65(m,2H),2.60(d,J＝17.2Hz,2H),2.38(dd,J＝17.5,8.4Hz,2H),2.00(s,1H).LCMS(ESI)C 32 H 29 ClF 3 N 4 O 4 + [M+H] + Calculated 625.18, measured 625.2.
Example 330: preparation of 3- (5- ((4- ((2- (furan-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05790)
The title compound (GT-05790) (white solid, 49mg, yield 63.42%) was prepared according to the method of scheme 1. 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),7.89–7.77(m,2H),7.71(s,2H),6.55(d,J＝13.4Hz,2H),5.14(dd,J＝13.3,5.1Hz,1H),4.43(dd,J＝51.1,17.6Hz,4H),4.04(s,3H),3.49(s,4H),3.33–3.28(m,2H),2.97–2.87(m,1H),2.61(d,J＝18.2Hz,2H),2.43(dd,J＝13.3,4.5Hz,1H),2.36(s,2H),2.16(s,2H),2.04–1.95(m,1H),1.40(t,J＝6.2Hz,2H),0.94(s,6H).LCMS(ESI)C 31 H 39 N 4 O 4 + [M+H] + Calculated 531.30, measured 531.3.
Example 331: preparation of 3- (5- ((4, 4-dimethyl-2- (thiazol-5-yl) cyclohex-1-en-1-yl) methyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05791)
Preparation of the target Compound (GT-05791) (white solid, 31mg, yield) according to the method of Synthesis scheme 139.02％)。 1 H NMR(400MHz,DMSO)δ11.01(s,1H),9.15(s,1H),7.86(s,1H),7.81(d,J＝7.8Hz,1H),7.74(d,J＝6.0Hz,2H),5.14(dd,J＝13.3,5.1Hz,1H),4.49(d,J＝17.3Hz,3H),4.37(d,J＝17.6Hz,1H),3.50(s,7H),3.15(s,2H),2.98–2.87(m,1H),2.61(d,J＝17.5Hz,2H),2.43(d,J＝16.9Hz,3H),2.10(s,2H),2.04–1.97(m,1H),1.44(t,J＝6.0Hz,2H),0.94(s,6H).LCMS(ESI)C 30 H 38 N 5 O 3 S + [M+H] + Calculated 548.27, found 548.3.
Example 332: preparation of 3- (1-oxo-5- ((4- ((4 ', 5-trimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) methyl) isoindolin-2-yl) piperidine-2, 6-dione (GT-05792)
The title compound (GT-05792) was prepared according to the method of scheme 1 (white solid, 46mg, yield 57.26%). 1 H NMR(400MHz,DMSO)δ11.01(s,1H),7.79(d,J＝7.7Hz,2H),7.66(s,1H),7.17(d,J＝7.7Hz,2H),6.97(d,J＝7.7Hz,2H),5.13(dd,J＝13.4,5.1Hz,1H),4.41(dd,J＝51.0,17.5Hz,3H),4.29–4.08(m,1H),3.51(s,4H),3.24–3.11(m,2H),2.91(dd,J＝21.7,9.1Hz,2H),2.61(d,J＝17.7Hz,2H),2.42(dd,J＝17.3,8.6Hz,2H),2.30(s,5H),2.01(s,3H),1.45(d,J＝5.7Hz,2H),1.28(dd,J＝10.6,6.6Hz,1H),0.95(s,6H).LCMS(ESI)C 34 H 43 N 4 O 3 + [M+H] + Calculated 555.33, measured 555.3.
Example 333: preparation of 2- (2, 6-dioxopiperidin-3-yl) -5- ((4- ((4 ', 5-trimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) methyl) isoindoline-1, 3-dione (GT-05793)
The title compound (GT-05793) was prepared according to the method of scheme 1 (white solid, 14mg, yield 19.14%). 1 H NMR(400MHz,DMSO)δ11.14(s,1H),8.00(d,J＝31.0Hz,3H),7.18(d,J＝7.7Hz,2H),6.97(d,J＝7.6Hz,2H),5.17(dd,J＝12.7,5.3Hz,1H),4.19(s,2H),3.52(s,2H),3.33–3.26(m,2H),3.20–2.97(m,3H),2.91(dd,J＝22.1,9.0Hz,2H),2.80–2.70(m,1H),2.58(dd,J＝23.3,11.2Hz,3H),2.31(s,5H),2.10–2.04(m,1H),2.01(s,2H),1.45(d,J＝5.8Hz,2H),0.95(s,6H).LCMS(ESI)C 34 H 41 N 4 O 4 + [M+H] + Calculated 569.31, measured 569.3.
Example 334: preparation of 2- (2, 6-dioxopiperidin-3-yl) -5- (4- ((4 ', 5-trimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazine-1-carbonyl) isoindoline-1, 3-dione (GT-05794)
The title compound (GT-05794) (white solid, 25mg, yield 30.59%) was prepared according to the procedure of synthesis scheme 6 and example 76. 1 H NMR(400MHz,DMSO)δ11.15(s,1H),10.24(s,1H),8.05–7.92(m,2H),7.88(d,J＝7.7Hz,1H),7.21(d,J＝7.6Hz,2H),7.00(d,J＝7.5Hz,2H),5.18(dd,J＝12.8,5.4Hz,1H),4.45(s,1H),3.62(s,4H),3.47(s,2H),3.23–3.16(m,1H),2.96–2.82(m,2H),2.67(s,1H),2.65–2.55(m,2H),2.41(s,1H),2.31(d,J＝7.4Hz,3H),2.29–2.19(m,1H),2.10–1.96(m,3H),1.47(s,2H),0.96(s,6H).LCMS(ESI)C 34 H 39 N 4 O 5 + [M+H] + Calculated 583.29, found 583.3.
Example 335: preparation of 3- (5- (5- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -2, 5-diazabicyclo [2.2.2] octane-2-carbonyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05795)
The title compound (GT-05795) (white solid, 32mg, yield 35.33%) was prepared according to the procedure of synthesis scheme 6 and example 76. 1 H NMR(400MHz,DMSO-d6)δ11.03(d,J＝12.0Hz,1H),9.89(s,1H),7.81(dd,J＝9.8,5.5Hz,1H),7.60(d,J＝19.4Hz,1H),7.51(dd,J＝13.5,5.4Hz,1H),7.46(d,J＝8.1Hz,1H),7.25–7.11(m,2H),5.14(dd,J＝12.5,4.3Hz,1H),4.51(dd,J＝16.6,7.7Hz,1H),4.38(dd,J＝17.7,3.4Hz,1H),3.84–3.63(m,4H),3.59–3.39(m,2H),3.29–3.10(m,1H),3.06–2.84(m,2H),2.61(d,J＝16.6Hz,1H),2.48–2.15(m,4H),2.13–1.88(m,4H),1.81(s,1H),1.53–1.40(m,2H),1.31(s,1H),0.92(s,6H).LCMS(ESI)C 35 H 40 ClN 4 O 4 + [M+H] + Calculated 615.27, measured 615.3.
Example 336: preparation of 3- (5- ((4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -2- (trifluoromethyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05796)
The title compound (GT-05796) (white solid, 5.9mg, yield 23.54%) was prepared according to the method of FIG. 1. 1 H NMR(400MHz,DMSO)δ10.99(s,1H),7.69(d,J＝7.7Hz,1H),7.52(s,1H),7.43(d,J＝7.6Hz,3H),7.10(s,2H),5.10(dd,J＝13.3,5.2Hz,1H),4.37(dd,J＝52.3,17.3Hz,3H),4.02(s,2H),3.13–2.98(m,1H),2.90(dd,J＝22.2,9.1Hz,2H),2.79(s,2H),2.68–2.54(m,3H),2.44–2.32(m,2H),2.29–2.17(m,1H),2.01(s,4H),1.44(s,2H),0.94(s,6H).LCMS(ESI)C 34 H 39 ClF 3 N 4 O 3 + [M+H] + Calculated 643.27, measured 643.3.
Example 337: preparation of 3- (5- ((4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -2- (trifluoromethyl) piperazin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-06100)
The title compound (GT-06100) was prepared according to the procedure of scheme 1 (white solid, 14mg, yield 21.92%). 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),10.38(s,1H),7.58(s,2H),7.40(s,2H),7.09(s,2H),5.14–5.06(m,1H),4.55(d,J＝17.4Hz,1H),4.37(d,J＝17.4Hz,1H),4.00(s,2H),3.62(s,2H),3.39(s,2H),3.10(s,1H),2.97–2.74(m,3H),2.63(t,J＝17.8Hz,3H),2.39(dd,J＝30.6,16.6Hz,2H),2.22(s,1H),2.01(s,3H),1.44(s,2H),0.95(s,6H).LCMS(ESI)C 34 H 38 ClF 4 N 4 O 3 + [M+H] + Calculated 661.26, measured 661.3.
Example 338: preparation of 3- (5- ((4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -2- (trifluoromethyl) piperazin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-06101)
The title compound (GT-06101) was prepared according to the procedure of scheme 1 (white solid, 17.6mg, yield 27.56%). 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),10.73(s,1H),7.64(d,J＝6.0Hz,1H),7.50(d,J＝8.7Hz,1H),7.41(d,J＝7.3Hz,2H),7.10(s,2H),5.11(dd,J＝13.1,4.9Hz,1H),4.37(dd,J＝49.8,17.4Hz,2H),4.00(s,2H),3.54(s,3H),3.09(s,2H),2.98–2.78(m,3H),2.60(d,J＝16.5Hz,3H),2.39(dt,J＝26.8,13.4Hz,2H),2.25(s,1H),2.01(s,3H),1.44(s,2H),0.95(s,6H).LCMS(ESI)C 34 H 38 ClF 4 N 4 O 3 + [M+H] + Calculated 661.26, measured 661.3.
Example 339: preparation of 3- (5- ((4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -2- (trifluoromethyl) piperazin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-06102)
The title compound (GT-06102) was prepared according to the procedure of scheme 1 (white solid, 9mg, yield 14.09%). 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),10.54(s,1H),7.42(s,2H),7.35(s,1H),7.20(d,J＝10.3Hz,1H),7.10(s,2H),5.07(d,J＝8.6Hz,1H),4.45(d,J＝17.4Hz,1H),4.32(d,J＝17.4Hz,1H),4.03(s,2H),3.63(s,3H),3.06(s,1H),2.99–2.78(m,3H),2.62(t,J＝19.1Hz,3H),2.37(d,J＝12.4Hz,2H),2.27–2.12(m,1H),2.01(s,4H),1.44(s,2H),0.95(s,6H).LCMS(ESI)C 34 H 38 ClF 4 N 4 O 3 + [M+H] + Calculated 661.26, measured 661.3.
Example 340: preparation of 5- ((4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -2- (trifluoromethyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-06103)
The title compound (GT-06103) was prepared according to the procedure of scheme 1 (white solid, 9.5mg, yield 14.96%). 1 H NMR(400MHz,DMSO-d6)δ11.12(s,1H),7.82(dd,J＝27.3,11.8Hz,4H),7.42(s,2H),7.09(s,2H),5.46–4.96(m,2H),4.09(s,2H),3.73(s,2H),3.11(s,2H),2.87(d,J＝13.8Hz,3H),2.72–2.53(m,4H),2.33(s,2H),2.01(s,4H),1.44(s,2H),0.95(s,6H).LCMS(ESI)C 34 H 37 ClF 3 N 4 O 4 + [M+H] + Calculated 657.24, measured 657.3.
Example 341: preparation of 3- (5- ((4- (4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) -2- (trifluoromethyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05845)
The title compound (GT-05845) (white solid, 5.6mg, 17.94% yield) was prepared according to the procedure of FIG. 1. 1 H NMR(400MHz,DMSO-d6)δ10.98(s,1H),7.67(d,J＝7.7Hz,1H),7.50(d,J＝8.0Hz,1H),7.40(dd,J＝16.1,8.7Hz,3H),7.22(dd,J＝19.1,8.1Hz,2H),5.17–5.00(m,1H),4.43(d,J＝17.4Hz,1H),4.30(d,J＝17.3Hz,1H),4.00–3.65(m,3H),3.54(s,1H),3.37(s,2H),3.19(s,1H),2.90(dd,J＝21.5,9.5Hz,1H),2.60(d,J＝16.5Hz,3H),2.38(dd,J＝24.9,15.7Hz,3H),2.17–1.87(m,3H),1.44(s,2H),1.09(s,6H).LCMS(ESI)C 34 H 37 ClF 3 N 4 O 4 + [M+H] + Calculated 657.24, measured 657.3.
Example 342: preparation of 3- (5- ((4- ((4 '-fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -2- (trifluoromethyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05846)
The title compound (GT-05846) (white solid, 11.3mg, yield 32.96%) was prepared according to the method of scheme 1. 1 H NMR(400MHz,DMSO-d6)δ10.99(s,1H),7.69(d,J＝7.6Hz,1H),7.52(s,1H),7.43(d,J＝7.9Hz,1H),7.14(d,J＝36.3Hz,5H),5.10(dd,J＝13.2,5.2Hz,1H),4.43(d,J＝17.2Hz,1H),4.30(d,J＝17.4Hz,1H),4.02(s,2H),2.93(d,J＝13.5Hz,2H),2.78(s,2H),2.60(d,J＝16.8Hz,2H),2.38(dd,J＝20.3,11.1Hz,3H),2.28–2.14(m,2H),2.01(s,4H),1.44(s,2H),0.94(s,6H).LCMS(ESI)C 34 H 39 F 4 N 4 O 3 + [M+H] + Calculated 627.30, measured 627.3.
Example 343: preparation of 3- (5- ((4, 4-dimethyl-2- (thiophen-2-yl) cyclohex-1-en-1-yl) methyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05847)
The title compound (GT-05847) was prepared according to the procedure for synthesis scheme 1 (white solid, 41mg, yield 48.30%). 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),7.79(d,J＝7.7Hz,2H),7.70(s,1H),7.54(d,J＝4.8Hz,1H),7.11–6.97(m,1H),6.92(s,1H),5.14(dd,J＝13.3,5.1Hz,1H),4.49(d,J＝17.6Hz,1H),4.36(d,J＝17.5Hz,2H),3.59(s,2H),3.46(s,4H),3.36–3.27(m,4H),3.00–2.86(m,2H),2.61(d,J＝16.8Hz,1H),2.43(dd,J＝13.1,4.5Hz,1H),2.34(s,2H),2.11(s,2H),2.04–1.95(m,1H),1.43(t,J＝6.1Hz,2H),0.94(s,6H).LCMS(ESI)C 31 H 39 N 4 O 3 S + [M+H] + Calculated 547.27, found 547.3.
Example 344: preparation of 3- (5- ((4, 4-dimethyl-2- (oxazol-5-yl) cyclohex-1-en-1-yl) methyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05848)
The title compound (GT-05848) was prepared according to the method of scheme 1 (white solid, 11.7mg, yield 28.46%). 1 H NMR(400MHz,DMSO)δ11.01(s,1H),8.35(s,1H),7.85(s,1H),7.80(d,J＝7.7Hz,1H),7.75(s,1H),7.31(s,1H),5.14(dd,J＝13.4,5.0Hz,1H),4.43(dd,J＝51.3,17.6Hz,5H),3.94(s,3H),3.58(s,3H),3.00–2.84(m,2H),2.61(d,J＝17.9Hz,3H),2.46–2.36(m,3H),2.16(s,2H),2.04–1.96(m,1H),1.41(t,J＝5.9Hz,2H),0.94(s,6H).LCMS(ESI)C 30 H 38 N 5 O 4 + [M+H] + Calculated 532.29, measured 532.3.
Example 345: preparation of 3- (5- ((4- (2- (oxazol-5-yl) benzyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05849)
The title compound (GT-05849) was prepared according to the method of scheme 1 (white solid, 33mg, yield 42.08%). 1 H NMR(400MHz,DMSO)δ11.01(s,1H),8.52(s,1H),7.88(s,1H),7.78(dd,J＝18.6,9.2Hz,4H),7.65(s,1H),7.52(dt,J＝19.6,7.1Hz,2H),5.14(dd,J＝13.3,5.1Hz,1H),4.49(d,J＝17.4Hz,3H),4.36(d,J＝17.6Hz,3H),3.41–3.19(m,6H),2.99–2.84(m,1H),2.61(d,J＝16.9Hz,1H),2.43(dd,J＝13.2,4.4Hz,1H),2.05–1.92(m,1H).LCMS(ESI)C 28 H 30 N 5 O 4 + [M+H] + Calculated 500.23, found 500.2.
Example 346: preparation of 3- (5- (3- (4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) -3, 6-diazabicyclo [3.1.1] heptane-6-carbonyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05538)
Reference to Synthesis scheme 6 and implementationThe procedure of example 76 gave the title compound (GT-05538) (white solid, 29mg, yield 34%). 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),7.88–7.64(m,2H),7.50(d,J＝14.3Hz,1H),7.38(d,J＝6.6Hz,2H),7.32–7.22(m,2H),5.16–5.13(m,1H),4.66–4.22(m,4H),3.58–3.51(m,1H),2.92(t,J＝15.5Hz,1H),2.63–2.59(m,2H),2.46–2.36(m,4H),2.28–2.14(m,1H),2.07–2.01(m,1H),1.97–1.73(m,2H),1.59–1.21(m,4H),0.99–0.93(m,6H).LCMS(ESI)C 34 H 36 ClN 4 O 5 + [M+H] + Calculated 615.24, measured 615.3.
Example 347: preparation of 3- (5- (3- (4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) -3, 8-diazabicyclo [3.2.1] octane-8-carbonyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05539)
The title compound (GT-05539) (white solid, 34mg, 41% yield) was prepared according to the procedure of synthesis scheme 6 and example 76. 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),7.77(d,J＝7.2Hz,1H),7.67(s,1H),7.55(d,J＝7.6Hz,1H),7.41–7.35(m,3H),7.21–7.14(m,1H),5.13(dd,J＝13.0,4.9Hz,1H),4.64–4.30(m,3H),3.98–3.77(m,2H),3.20(brs,1H),2.95–2.87(m,2H),2.61(d,J＝16.7Hz,1H),2.49–2.40(m,4H),2.28–2.24(m,1H),2.17–2.11(m,1H),2.16–2.08(m,1H),1.93–1.85(m,2H),1.61–1.27(m,4H),0.96(s,6H).LCMS(ESI)C 35 H 38 ClN 4 O 5 + [M+H] + Calculated 629.25, measured 629.3.
Example 348: preparation of 3- (5- (8- (4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) -3, 8-diazabicyclo [3.2.1] octane-3-carbonyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05540)
The title compound (GT-05540) (white solid, 29mg, yield 35%) was prepared according to the procedure of synthesis scheme 6 and example 76. 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),7.76(d,J＝7.7Hz,1H),7.56(brs,1H),7.46–7.33(m,3H),7.29–7.23(m,2H),5.13(dd,J＝13.3,5.2Hz,1H),4.56–4.13(m,4H),3.88–3.67(m,1H),3.25–3.20(m,1H),3.17–3.13(m,1H),2.95–2.87(m,1H),2.50–2.45(m,2H),2.46–2.35(m,2H),2.30–2.18(m,2H),2.07–1.94(m,2H),1.53–1.33(m,5H),0.99–0.94(m,6H).LCMS(ESI)C 35 H 38 ClN 4 O 5 + [M+H] + Calculated 629.25, measured 629.3.
Example 349: preparation of 3- (1-oxo-5- ((4- (5-phenylpyrazine-2-carbonyl) piperazin-1-yl) methyl) isoindolin-2-yl) piperidine-2, 6-dione (GT-05635)
The title compound (GT-05635) was prepared according to the method of scheme 6 (white solid, 58mg, 63% yield). 1 H NMR(400MHz,DMSO-d6)δ11.50(s,1H),11.01(s,1H),9.29(d,J＝1.4Hz,1H),8.96(d,J＝1.3Hz,1H),8.21(dd,J＝7.6,1.9Hz,2H),7.91–7.80(m,2H),7.75(d,J＝7.7Hz,1H),7.63–7.51(m,3H),5.15(dd,J＝13.3,5.1Hz,1H),4.62(brs,1H),4.56–4.34(m,4H),4.23–4.19(m,1H),3.68(t,J＝15.4Hz,1H),3.54–3.44(m,3H),3.23–3.14(m,2H),3.02–2.84(m,1H),2.61(d,J＝17.5Hz,1H),2.47–2.35(m,1H),2.09–1.92(m,1H).LCMS(ESI)C 29 H 29 N 6 O 4 + [M+H] + Calculated 525.22, measured 525.3.
Example 350: preparation of 3- (7- ((5- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -2, 5-diazabicyclo [2.2.2] octane-2-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05462)
The title compound (GT-05462) was prepared according to the method of scheme 1 (white solid, 9mg, yield 20.66%). 1 H NMR(400MHz,DMSO)δ11.69(s,1H),11.05(s,1H),7.94(s,1H),7.72(s,2H),7.52–7.30(m,2H),7.21(s,2H),5.01(d,J＝121.5Hz,3H),4.46(d,J＝31.8Hz,2H),3.72(d,J＝31.3Hz,7H),2.97(dd,J＝50.9,37.5Hz,2H),2.75–2.59(m,2H),2.33(s,2H),2.25–1.83(m,6H),1.39(d,J＝47.0Hz,3H),0.96(s,6H).LCMS(ESI)C 35 H 42 ClN 4 O 3 + [M+H] + Calculated 601.29, found 601.3.
Example 351: preparation of 3- (7- ((4- (4 '-fluoro-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-carbonyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-05469)
Preparation by the method according to FIG. 6The title compound (GT-05469) was prepared (white solid, 22mg, yield 29.12%). 1 H NMR(400MHz,DMSO)δ11.56(s,1H),11.05(s,1H),10.42(s,1H),7.71(d,J＝5.8Hz,3H),7.16(dd,J＝58.3,30.6Hz,4H),5.12(s,1H),4.89–4.23(m,6H),3.73(d,J＝13.6Hz,2H),3.43–2.88(m,6H),2.61(s,2H),2.05(s,4H),1.71(s,4H).LCMS(ESI)C 31 H 34 FN 4 O 4 + [M+H] + Calculated 545.26, measured 545.3.
Biological Activity assay
Experimental reagents and materials:
the experimental method comprises the following steps:
cell culture
In the cell culture medium of Table A below, in the presence of 5% CO 2 The tumor cells used in the present disclosure were cultured in 37℃incubators, respectively. All cells were identified as correct by STR and were mycoplasma negative by mycoplasma detection kit prior to the experiment.
Table a tumor cells and cell culture media used in the present disclosure
I. half-Inhibitory Concentration (IC) of compound against tumor cells 50 ) And (3) measuring:
IC of the compounds of the present disclosure (including the compounds of Table 1 and the compounds of the examples) 50 The assay was performed using the Meinai Biol.S. Meilun Cell Counting Kit-8 kit. The method comprises the following specific steps: tumor cells were seeded in 96-well cell culture plates at the seeding densities of table B, respectively. The next day, the test compounds of the present disclosure were subjected to 5-fold gradient dilution from the highest concentration of 10. Mu.M, from high to lowA total of 10 concentrations were set and then 0.5 μl of diluted compounds of the present disclosure (including compounds of table 1 and compounds of the examples) was added to 100 μl of inoculated cells. After a period of treatment of cells with a compound of the present disclosure, cell activity assays were performed according to the instructions of the CCK-8 kit. The negative control was DMSO and the control was the corresponding commercial inhibitor (including lenalidomide (CAS number: 191732-72-6) and pomalidomide (CAS number: 19171-19-8)), which were treated with the same treatment as the disclosed compounds. Inhibition of cell growth by compounds of the present disclosure was plotted by Prism Graphpad software and compound IC of the present disclosure was counted therefrom 50 。
Table B procedure and treatment time for seeding tumor cells
The results of inhibiting tumor cell proliferation are listed in table C.
Table C inhibitory Activity of the inventive Compounds against tumor cell proliferation (IC 50 ,nM)
In table C, the symbols A1, A2, A3, A4, B, C, D, E and F have the following meanings: 0nM < A1 < 5nM; a2 is 5nM less than or equal to 10nM; a3 is less than or equal to 50nM and 10nM; 50nM < A4 < 100nM;100nM < B < 500nM;500nM < C.ltoreq.1000 nM;1000nM < D < 5000nM;5000nM < E.ltoreq.10000 nM;10000nM < F.
The results show that the compounds (including the compounds in table 1 and the compounds in examples) can inhibit the proliferation of tumor cells (shown in table C), the inhibition effect is superior or equivalent to that of the corresponding positive control drug, and the degradation effect is superior to that of the corresponding positive control drug. The results show that the compounds of the present invention (including the compounds of table 1 and the compounds of examples) have significant inhibitory effects on proliferation of mm.1s cells (human multiple myeloma cells), mm.1r cells (human multiple myeloma cells-dexamethasone resistant), kasumi-1 cells (human acute lymphoblastic leukemia cells), daudi cells (human Burkitt's lymphoma cells), TMD8 cells (human diffuse large B lymphoma cells), ramos cells (human B lymphoma cells), MDA-MB-231 cells (human breast cancer cells), mino cells (human mantle cell lymphoma cells), SU-DHL-4 cells (human B lymphoma cells), SU-DHL-6 cells (human diffuse large B lymphoma cells), SW620 cells (human colon cancer cells), MV-4-11 cells (human myelomonocytic leukemia cells) and CCRF-CEM cells (human acute lymphoblastic leukemia T lymphocytes) (as shown in table C), which are superior to the corresponding positive control drugs.
Binding affinity assay of compounds for CRBN:
the CRBN binding ability of the test compounds was measured by HTRF (homogeneous time-resolved fluorescence) method using CEREBLON BINDING KITS kit (Specification 10,000tests; reagent code: 64 BDCRBNPER; supplier CISBIO Co.), as follows:
1. test compounds of the present disclosure and lenalidomide were serially diluted with a diluet #9 (1X) solution according to the instructions of CEREBLON BINDING KITS kit to obtain a test compound and lenalidomide solution at a final concentration of 2 μm.
2. 2.5. Mu.L of the above 2. Mu.M test compound and lenalidomide solution and the same volume of the dilutent #9 (1X) solution (solvent control, std 0) were added to each well of the 96-well plate, respectively. Then, 2.5. Mu.L of human Cereblon WT GST-tagged protein solution was added to each well. Finally, 5. Mu.L of the well-mixed Thalidomide-Red reagent and GST Eu antibody working solution were added to each well. The final concentration of test compound and lenalidomide in each well was 0.5 μm.
3. The blank wells were sequentially filled with 2.5. Mu.L of the diluent #9 (1X) solution, 2.5. Mu.L of the PROTAC binding buffer solution, and 5. Mu.L of the well-mixed Thalimide-Red reagent and GST Eu antibody working solution, respectively.
4. After the solution in each well was incubated at room temperature for 3 hours in a sealed manner, absorbance values at emission wavelengths of 620nm and 665nm were measured by HTRF method using Spark microplate reader (V3.1SP1), respectively.
The corresponding CRBN binding inhibition rate was calculated using the following method: r is R Compounds of formula (I) ＝OD 665nm Compounds of formula (I) /OD 620nm Compounds of formula (I) -OD 665nm Control /OD 620nm Control R Std0 ＝OD 665nm Std0 /OD 620nm Std0 -OD 665nm Control /OD 620nm Control Inhibition ratio (%) = (1-R Compounds of formula (I) /R Std0 )*100
Note that: OD 665nm Compounds of formula (I) Is the absorbance value of each hole of the compound to be tested at the emission wavelength of 665nm
OD 620nm Compounds of formula (I) Is the absorbance value of each hole of the compound to be tested at the emission wavelength of 620nm
OD 665nm Control Is the absorbance value of the blank control hole at the emission wavelength of 665nm
OD 620nm Control Is the absorbance value of the blank control hole at the emission wavelength of 620nm
OD 665nm Std0 Is the absorbance value of the solvent control well at the emission wavelength of 665nm
OD 620nm Std0 Is the absorbance value of the solvent control well at the emission wavelength of 620nm
The results are set forth in Table D below.
Table D HTRF inhibitory activity (IC) of the compounds of the present invention (including, but not limited to, the compounds of table 1 and the compounds of the examples) 50 ,μM)
Experimental results show that the compounds of the present disclosure (including the compounds of table 1 and the compounds of the examples) have strong binding forces to CRBN.
III Western immunoblot (Western Blot) assay
The effect of the compounds of the present disclosure on target protein expression in cells was detected using conventional Western immunoblotting (Western Blot).
The inoculation number is 5×10 5 After 24 hours of incubation with hBMC, cells were treated with concentrations of the disclosed compounds (including the compounds of Table 1 and the compounds of the examples) of (1) 500nM or (2) serial dilutions of the disclosed compounds, i.e., 0.03nM, 0.1nM, 0.3nM, 1nM, 3nM, 10nM, 30nM, 100nM, 300nM and 1000nM. The negative control was DMSO and the positive control was the corresponding commercial immunomodulatory drug (lenalidomide), pomalidomide, all treated cells in the same manner as the presently disclosed compounds. After 24 hours of compound treatment, the cells were collected, lysed by addition of RIPA protein lysate containing phosphatase inhibitors, and placed on ice for 30-60 minutes, and centrifuged. The supernatant was collected, and the resulting supernatant was the total cell protein extracted. The protein concentration of the supernatant was determined by the conventional BCA method (Bicinchoninc acid procedure). Adding 4X SDS sample solution into the supernatant, carrying out denaturation treatment at 95 ℃ for 5 minutes, carrying out polyacrylamide gel SDS-PAGE electrophoresis, transferring to a nitrocellulose membrane (NC membrane), sealing for 1-2 hours at normal temperature by using sealing solution, and then carrying out operation methods such as antibody incubation, development and the like according to the antibody instruction of Cell Signaling Technology company.
Half-degradation concentration (concentration of drug corresponding to 50% protein degradation, i.e., DC 50 ) The reading method comprises the following steps: comparing the gray value of the corresponding Western blotting strip after the drug treatment with the gray value of the corresponding Western blotting strip after the blank DMSO treatment, wherein the read gray value is corresponding Wes after the blank DMSO treatmentthe drug concentration range for the term blotting band when the gray value is half.
DC 50 The value can be calculated by using imageJ software to read the gray value of the corresponding Western blotting band after the drug treatment. And (5) fitting a relation curve between the drug concentration and the gray value to calculate the drug concentration when the corresponding gray value is half.
The effect of the compounds of the present disclosure (including the compounds of table 1 and the compounds of the examples) on the expression of substrate proteins in hPBMC cells at a concentration of 500nM is shown in table E below.
Table E degradation results of the substrate proteins by the compounds of the invention at 500nM concentration levels
In Table E, A represents the remaining amount of substrate protein <50%, and B represents the remaining amount of substrate protein >50%.
Experimental results show that the compounds of the present disclosure (including the compounds of table 1 and the compounds of the examples) can effectively degrade substrate proteins (e.g., IKZF1/3 proteins, GSPT1 proteins, etc.) at 500nM concentrations.
The inventors further examined the effect of serial dilutions (i.e., 0.03nM, 0.1nM, 0.3nM, 1nM, 3nM, 10nM, 30nM, 100nM, 300nM and 1000 nM) of the compounds of the present disclosure on target protein expression in hBMC cells. Western Blot results are shown in FIG. 1. As shown in FIG. 1, lenalidomide cannot degrade IKZF1/3 protein and GSPT1 protein at 50nM and 500nM concentration levels, pomalidomide cannot degrade IKZF1/3 protein and GSPT1 protein at 50nM concentration levels, whereas the compounds of the present disclosure can significantly degrade IKZF1/3 protein and GSPT1 protein (FIG. 1), especially the compounds of the present disclosure GT-04194 exhibit significant degradation at concentrations below 30nM, and the compounds of the present disclosure GT-05640, GT-05596, GT-05598, GT-05620 exhibit significant degradation at concentrations below 0.1nM, 0.3nM or 3 nM. The Western Blot experiment results show that compared with lenalidomide and pomalidomide, the compound disclosed by the invention has the advantages of remarkably improving the activity in the aspects of inhibiting tumor cells and inducing degradation of substrate proteins.
Pharmacokinetic studies of the compounds of the present disclosure
Pharmacokinetic properties of the compounds of the present disclosure were tested using conventional pharmacokinetic experimental methods.
Test compounds of the present disclosure (including the compounds of table 1 and the compounds of the examples) were orally administered to experimental animals and the pharmacokinetic properties of the compounds of the present disclosure were evaluated. The experimental animals used may be adult healthy rodents (e.g., mice, rats (e.g., sprague-Dawley (SD) rats), guinea pigs), or non-rodents (rabbits, dogs, and monkeys) as are commonly used in pharmacokinetic experiments. The experimental animal employed in the present disclosure is a mouse.
The experimental animals were divided into 2 groups, namely a control group (blank plasma collection) and an oral administration group (administration dose is 10mg/kg or 30 mg/kg). Blood samples are collected at predetermined sampling time points after administration, for example, blood collection time points are: 0.25h, 0.5h, 1h, 2h, 4h, 8h, 24h after administration. Blank plasma was collected from the control group.
Pretreatment of plasma samples prior to analysis: to 10. Mu.L of plasma sample was added 10. Mu.L of 50% acetonitrile and 200. Mu.L of an internal standard solution (the internal standard solution was an acetonitrile solution containing 50ng/ml dexamethasone). The plasma samples of the blank group were supplemented with the same volume of acetonitrile without the internal standard. And (3) mixing the treated samples uniformly by vortex, centrifuging, and taking supernatant for LC-MS/MS sample injection analysis.
After preparation of standard curves and QC samples, LC-MS/MS analysis was used to determine the compound concentration in the plasma samples tested. According to the blood concentration data determined by LC-MS/MS analysis, pharmacokinetic parameters of the compound to be tested are calculated respectively by using a pharmacokinetic calculation software WinNonlin v8.1 non-atrioventricular model. The results are set forth in Table F below.
Table F pharmacokinetic parameters of compounds of the present disclosure in mouse plasma
Note that: in table F, p.o. indicates oral administration, a indicates >500h ng/mL, and B indicates +.500h ng/mL.
The results show that the compounds of the present disclosure administered via the oral route of administration have good pharmacokinetic (DMPK) profiles and can be used as therapeutic drugs for oncology patients.
V. Effect of the compounds of the present disclosure on lipopolysaccharide or phytohemagglutinin induced PBMC release of TNF- α, IL-10, IL-6, IL-1β, IFN- γ, GM-CSF, IL-2 and IL-12p40
The following materials were used in this study:
v.1 reagents and consumables
V.2 method
V.2.1 cell resuscitations and plating
Preparing a complete culture medium, and preheating at 37 ℃ for later use; taking out cells from a liquid nitrogen tank, clamping the position just below the boundary line between the cover of the freezing storage tube and the bottle body by using forceps, immersing the cells in warm water at 37 ℃ and shaking the cells from time to enable the cells to be melted as soon as possible; sucking out the cell suspension, adding the cell suspension into a centrifuge tube containing 10mL of complete culture medium, and uniformly mixing; centrifuging at room temperature for 10min at 400 g; the supernatant was discarded, complete medium was added, cell density was counted and adjusted, and inoculated into 96-well plates at 75. Mu.L/well to a cell number of 1X 10 per well 5 High humidity, 37 ℃,5% CO 2 The incubator is subjected to stationary culture for 2 hours.
V.2.2 preparation of Compounds and addition to cell plates
1) Test compounds were formulated in DMSO as 10mM stock solutions.
2) The test compounds were diluted stepwise 5-fold with DMSO at the highest concentration of 1mM, giving 9 concentration gradients of the compound.
3) The test compounds were diluted with medium to 5 times the set final concentration of the corresponding effect.
4) The diluted compounds were added to the corresponding cell wells at 25. Mu.L/well according to the following layout. The final concentration of the compound was 1. Mu.M, 5-fold gradient dilution, and 9 concentration points total.
5) After 1h, LPS or PHA was added to the cell wells at 25. Mu.L/well to a final LPS concentration of 1. Mu.g/mL (TNF-. Alpha., IL-10, IL-6, GM-CSF and IL-12p 40), 5. Mu.g/mL (IL-1β), 50. Mu.g/mL (IFN-. Gamma.) and PHA concentration of 1. Mu.g/mL (IL-2), respectively.
6) Placing the cell plate in high humidity, 37 ℃ and 5% CO 2 Incubate for 24h.
Cell plate layout:
v.2.3 detection
(1) Centrifuging, sucking up the culture supernatant, and detecting TNF-alpha, IL-10, IL-6, IL-1β, IFN- γ, GM-CSF, IL-2 and IL-12p40 cytokines in the culture supernatant according to ELISA Kit instructions.
The concentrations of TNF- α, IL-10, IL-6, IL-1 β, IFN- γ, GM-CSF, IL-2 and IL-12p40 in the samples were calculated from the standard curve and the inhibition was = [ (Ac-As)/(Ac-Ab) ]. Times.100%
As: OA (cell+LPS/PHA+test Compound) of sample
Ac: OA of positive cell control (cell+LPS/PHA+DMSO)
Ab control OA (cell+Medium+DMSO)
(2) IC was performed using software Graphpad Prism 6 and using the calculation formula XY-analysis/Nonlinear regression (cut fit)/Dose response-Inhibition/log (inhibitor) vs. response-Variable slope (four parameters) 50 Curve fitting and calculation of IC 50 Values.
Experimental results show that the compounds of the present disclosure can regulate the production level of cytokines associated with autoimmune diseases, and can be used for treating autoimmune diseases.
VI. experiments on the efficacy of the Compounds of the present disclosure in imiquimod-induced psoriasis-like skin lesions in mice back
The compounds of the present disclosure (test subjects) were orally and gastro-orally administered to imiquimod-induced mice 1 time a day for 7 consecutive days, and the pharmacological effects of the compounds of the present disclosure on imiquimod-induced skin psoriasis-like lesions in the back of mice were studied.
90C 57BL/6J female mice (purchased from Shanghai Laek laboratory animal Co., ltd.) were equally divided into 9 groups according to body weight, 10 in each group:
note that: ig. the stomach is irrigated orally; sc. subcutaneous injection
After the experimental animals were grouped, the backs of all mice were shaved, and the animals of each group, except the Control group, were topically applied with imiquimod cream 1 time a day for 7 consecutive days. The solvent control, positive control or test agent was also administered 1 time per day for 7 consecutive days according to the above table, respectively.
All clinical symptoms of each animal were observed at the beginning of the experiment and during the course of the experiment. Animal weights were weighed and recorded 1 time a day 2.
Scoring of
Skin loss general appearance score (PASI method): the mice of each group were observed for changes in skin lesions 1 time per day for the last 3 days of model dosing. PASI method: and respectively scoring the erythema, the scale and the infiltration thickening degree at the skin damage position, and adding the three points to form a total point. PASI scoring criteria: 0 minutes, none; 1 min, slight; 2 minutes, moderately; 3 minutes, severe; 4 minutes, extremely severe.
The skin lesions were photographed 1 time a day for the last 3 days of the modelling dosing.
Mice were challenged with excess CO inhalation after the end of the experiment 2 Euthanasia was sacrificed. The skin at 3 different parts of the back skin lesion was weighed and recorded using a 6mm punch and the average weight calculated.
Skin tissue homogenates at skin lesions were examined for IL-23p19, IL-12p40, IL-17, TNF-alpha content.
Local skin injury part is obtained by HE staining after fixed material selection, and pathological scoring (epidermis thickness, epidermis cell keratinization degree, basal cell thickness, dermis inflammatory cell infiltration degree) is carried out, and scoring standard is that: 0 minutes, none; 1 min, slight; 2 minutes, moderately; 3 minutes, severe; 4 minutes, extremely severe.
Experimental data are expressed as mean±sd; data between the two groups were analyzed using SPSS statistics, p <0.05 was considered significant differences.
Experimental results show that the compound has an improving effect on the skin psoriasis-like lesions of the back of the mice induced by imiquimod, and can be used for treating psoriasis.
VII test of the efficacy of the Compounds of the present disclosure on type II collagen-induced CIA model rats
The compounds of the present disclosure (test subjects) were orally and gastrically administered to bovine type ii collagen (Chondrex corporation) -induced Wistar rats 1 time a day for 21 consecutive days, and the pharmacodynamic effects of the compounds of the present disclosure on the rat arthritis model (CIA) were studied.
Preparing a molding agent:
10mg of CII (Immunization Grade Bovine Type II Collagen, available from Chondrex) was dissolved in 5mL of 0.05M acetic acid solution and the solution was sufficiently dissolved to prepare a solution having a concentration of 2mg/mL, and left overnight at 4℃in the absence of light. In the test, 2mg/mL of CII solution was mixed with 4mg/mL of Complete Freund's Adjuvant (CFA, available from Chondrex) solution in equal volumes under ice bath conditions and emulsified thoroughly into an emulsion.
10 Wistar rats (purchased from beijing vernalia laboratory animal technologies limited) were randomly selected as a Control group on day 0 and were not immunized. The remaining 100 Wistar rats were given a first immunization by intradermal injection of an equal volume of an emulsion prepared by mixing clii (2 mg/mL) and CFA (4 mg/mL). A second boost was performed on day 7. On days 10-14, i.e. 3-7 days after the second boost, 80 animals were selected from the model animals with a disease foot AI (Arthritis Index) score of 1-2 minutes, and were divided into 8 groups according to body weight, foot volume and AI score, each group of 10:
And (3) injection: ig. the stomach is irrigated orally; sc. subcutaneous injection
3-7 days after the second immunization enhancement, starting to administer the solvent control, the positive control drug or the test substance to each group of animals according to the table by oral gavage (or subcutaneous injection) after the AI score of the disease foot reaches 1-2 times per day for 21 continuous days.
Starting 3 days after the second boost, the bilateral hind toe volumes were measured 2 times per week and recorded.
Foot volume measurement: before measurement, marking the position by marking a line at the ankle joint of the rat by using a marker pen, adding clean water into the instrument, and resetting the instrument numerical value to prepare for measurement. The hind limb of the rat is put into water so that the marking line at the ankle joint is positioned on the surface of the liquid, and the foot pedal reading is stepped on at the moment, so that the foot volume of the rat is obtained. After the measurement is finished, the pedal is stepped down again to clear the next piece to be measured.
Scoring of
Arthritis Index (AI): foot volumes were measured 2 times per week while four toe swellings were scored, 0-4 points per foot, with a maximum score of 16 points per rat.
Arthritis Index (Arthritis Index) scoring criteria:
the beginning of administration is marked as D0 day, and after 5 days of administration, namely 2 hours after D5 administration, the jugular vein of the experimental animal collects blood, stands for more than 30 minutes, separates serum by centrifugation, freezes at-80 ℃, and detects serum TNF-alpha, IL-1 beta and IL-6 by ELISA method.
After the experiment is finished, the animals adopt excessive CO inhalation 2 The method is euthanized. Spleen and thymus of the animal were collected, weighed and organ coefficients were calculated.
And (3) pathological detection: taking and fixing a lateral foot joint tissue in 10% neutral formalin solution, decalcification, and paraffin embedding, and performing HE staining for pathological observation.
And (3) observing the indexes:
1. synovial inflammatory cells (lymphocytes, plasma cells) infiltrate;
2. synovial tissue hyperplasia;
3. synovial pannus;
4. cellulose-like necrosis on the synovial surface.
The scoring and counting method comprises the following steps: five grades 0,1,2,3, 4: "0" is not seen; "1" mild; a "2" degree; "3" severe; "4" is extremely severe.
Experimental data are expressed as mean±sem; data between the two groups were analyzed using Excel-T test, with p <0.05 considered significant differences. Scoring data were analyzed using the SPSS nonparametric test Mann-Whitney U test, with p <0.05 considered significant differences.
Experimental results show that the compound disclosed by the invention can regulate the serum inflammatory factor level of bovine type II collagen-induced CIA model rats, has obvious improvement effect on limb swelling of rats, and can be used for treating arthritis.
The foregoing has shown and described the basic principles, principal features and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the above-described embodiments, and that various changes and modifications may be made therein without departing from the spirit and scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.

Claims (34)

式(I)化合物或其盐、对映异构体、非对映异构体、同位素富集类似物、溶剂化物、前药或多晶型物， A compound of formula (I) or a salt, enantiomer, diastereomer, isotopically enriched analog, solvate, prodrug or polymorph thereof, 其中in Rb1、Rb2、Rb3、Rb4、和Rb5各自独立地表示H、D或C1-3烷基；R b1 , R b2 , R b3 , R b4 , and R b5 each independently represent H, D or C 1-3 alkyl; X表示C(O)或CH2；X represents C(O) or CH 2 ; (Ra)n表示式(I)的苯环可选地被n个Ra取代，其中Ra表示氘、卤素、羟基、巯基、硝基、氨基、氰基、可选氘代的C1-6烷基、可选氘代的C1-6烷氧基、或卤代C1-6烷基，和n表示整数0、1、2、或3；以及( Ra ) n represents that the benzene ring of formula (I) is optionally substituted by n Ra , wherein Ra represents deuterium, halogen, hydroxyl, mercapto, nitro, amino, cyano, optionally deuterated C1-6 alkyl, optionally deuterated C1-6 alkoxy, or halogenated C1-6 alkyl, and n represents an integer of 0, 1, 2, or 3; and L1表示C(O)、亚烯基、可选取代的C1-5亚烷基、-CH＝、可选取代的C6-10亚芳基-C1-5亚烷基-*、或N(Rc1)，其中Rc1表示H或C1-3烷基，符号*表示与基团X1的连接点，或L1表示-C(RL1RL2)-，其中RL1、RL2连同它们连接的碳原子一起形成可选取代的C3-8亚环烷基，或L1表示键；L 1 represents C(O), alkenylene, optionally substituted C 1-5 alkylene, -CH=, optionally substituted C 6-10 arylene-C 1-5 alkylene-*, or N(R c1 ), wherein R c1 represents H or C 1-3 alkyl, the symbol * represents the point of connection to the group X 1 , or L 1 represents -C(R L1 R L2 )-, wherein R L1 , R L2 together with the carbon atom to which they are attached form an optionally substituted C 3-8 cycloalkylene, or L 1 represents a bond; X1表示可选取代的亚环烷基、可选取代的亚杂环基或可选取代的亚杂芳基；X 1 represents an optionally substituted cycloalkylene group, an optionally substituted heterocyclylene group or an optionally substituted heteroarylene group; X2表示C(O)、可选取代的C1-5亚烷基、可选取代的C3-8亚环烷基、可选取代的C1-2亚烷基-N(Rc2)-、-N(Rc2)-可选取代的C1-2亚烷基、或N(Rc3)，其中Rc2和Rc3各自独立地表示H或C1-3烷基，或者X2表示键； X2 represents C(O), optionally substituted C1-5 alkylene, optionally substituted C3-8 cycloalkylene, optionally substituted C1-2 alkylene-N( Rc2 )-, -N( Rc2 )-optionally substituted C1-2 alkylene, or N( Rc3 ), wherein Rc2 and Rc3 each independently represent H or C1-3 alkyl, or X2 represents a bond; Ra1表示以下结构： R a1 represents the following structure: 其中in 环A表示亚杂环基、亚环烷基、亚芳基、或亚杂芳基，(Rd1)m1表示环A可选地被m1个基团Rd1取代，m1表示0至10的整数，各Rd1独立地表示氘、羟基、氨基、巯基、卤素、氰基、氧代基、可选氘代的C1-6烷基、可选氘代的C3-6环烷基、可选氘代的C1-6烷氧基、卤代C1-6烷基、C1-4烷基-NH-、C1-4烷基-NHC(O)-、C1- 4烷基-C(O)NH-、或NH2-C1-6亚烷基-；和Ring A represents a heterocyclylene group, a cycloalkylene group, an arylene group, or a heteroarylene group, (R d1 ) m1 represents that Ring A is optionally substituted by m1 groups R d1 , m1 represents an integer from 0 to 10, and each R d1 independently represents deuterium, hydroxyl, amino, thiol, halogen, cyano, oxo, optionally deuterated C 1-6 alkyl, optionally deuterated C 3-6 cycloalkyl, optionally deuterated C 1-6 alkoxy, halogenated C 1-6 alkyl, C 1-4 alkyl-NH-, C 1-4 alkyl-NHC(O)-, C 1-4 alkyl-C(O)NH-, or NH 2 -C 1-6 alkylene-; and 环B表示芳基、环烷基、杂环基、或杂芳基，(Rd2)m2表示环B可选地被m2个基团Rd2取代，m2表示0至10的整数，各Rd2独立地表示氘、羟基、氨基、巯基、 卤素、氰基、氧代基、可选氘代的C1-6烷基、可选氘代的C3-6环烷基、可选氘代的C1-6烷氧基、卤代C1-6烷基、C1-4烷基-NH-、C1-4烷基-NHC(O)-、C1-4烷基-C(O)NH-、或NH2-C1-6亚烷基-；Ring B represents an aryl group, a cycloalkyl group, a heterocyclyl group, or a heteroaryl group, (R d2 ) m2 represents that Ring B is optionally substituted by m2 groups R d2 , m2 represents an integer from 0 to 10, and each R d2 independently represents deuterium, hydroxyl, amino, mercapto, halogen, cyano, oxo, optionally deuterated C 1-6 alkyl, optionally deuterated C 3-6 cycloalkyl, optionally deuterated C 1-6 alkoxy, halogenated C 1-6 alkyl, C 1-4 alkyl-NH-, C 1-4 alkyl-NHC(O)-, C 1-4 alkyl-C(O)NH-, or NH 2 -C 1-6 alkylene-; 其中当L1表示键时，X1表示可选取代的含氮亚桥杂环基；以及当X2表示键时，L1不为键。wherein when L 1 represents a bond, X 1 represents an optionally substituted nitrogen-containing subbridged heterocyclic group; and when X 2 represents a bond, L 1 is not a bond. 如权利要求1所述的式(I)化合物或其盐、对映异构体、非对映异构体、同位素富集类似物、溶剂化物、前药或多晶型物，其也是式(II)化合物或式(III)化合物： The compound of formula (I) or its salt, enantiomer, diastereomer, isotopically enriched analog, solvate, prodrug or polymorph as claimed in claim 1, which is also a compound of formula (II) or a compound of formula (III): 其中基团Rb1、Rb2、Rb3、Rb4、Rb5、(Ra)n、X、L1、X1、X2和Ra1如权利要求1所定义。wherein the groups R b1 , R b2 , R b3 , R b4 , R b5 , (R a ) n , X, L 1 , X 1 , X 2 and Ra1 are as defined in claim 1 . 如权利要求1所述的式(I)化合物或其盐、对映异构体、非对映异构体、同位素富集类似物、溶剂化物、前药或多晶型物，其也是式(Ia)、式(Ib)、式(Ic)、式(Id)、式(IIa)、式(IIb)、式(IIc)、式(IId)、式(IIIa)、式(IIIb)、式(IIIc)、或式(IIId)化合物： A compound of formula (I) or a salt, enantiomer, diastereomer, isotopically enriched analog, solvate, prodrug or polymorph thereof as claimed in claim 1, which is also a compound of formula (Ia), (Ib), (Ic), (Id), (IIa), (IIb), (IIc), (IId), (IIIa), (IIIb), (IIIc), or (IIId): 其中基团Rb1、Rb2、Rb3、Rb4、Rb5、(Ra)n、X、L1、X1、X2和Ra1如权利要求1所定义。wherein the groups R b1 , R b2 , R b3 , R b4 , R b5 , (R a ) n , X, L 1 , X 1 , X 2 and Ra1 are as defined in claim 1 . 如权利要求1-3中任一项所述的式(I)化合物或其盐、对映异构体、非对映异构体、同位素富集类似物、溶剂化物、前药或多晶型物，其中Rb1、Rb2、Rb3和Rb4各自独立地表示H，Rb5表示H或D。The compound of formula (I) or a salt, enantiomer, diastereomer, isotopically enriched analog, solvate, prodrug or polymorph thereof according to any one of claims 1 to 3, wherein R b1 , R b2 , R b3 and R b4 each independently represent H, and R b5 represents H or D. 如权利要求1-4中任一项所述的式(I)化合物或其盐、对映异构体、非对映异构体、同位素富集类似物、溶剂化物、前药或多晶型物，其中X表示C(O)。A compound of formula (I) or a salt, enantiomer, diastereomer, isotopically enriched analog, solvate, prodrug or polymorph thereof as claimed in any one of claims 1 to 4, wherein X represents C(O). 如权利要求1-4中任一项所述的式(I)化合物或其盐、对映异构体、非对映异构体、同位素富集类似物、溶剂化物、前药或多晶型物，其中X表示CH2。A compound of formula (I) or a salt, enantiomer, diastereomer, isotopically enriched analog, solvate, prodrug or polymorph thereof as claimed in any one of claims 1 to 4, wherein X represents CH 2 . 如权利要求1-6中任一项所述的式(I)化合物或其盐、对映异构体、非对映异构体、同位素富集类似物、溶剂化物、前药或多晶型物，其中A compound of formula (I) or a salt, enantiomer, diastereomer, isotopically enriched analog, solvate, prodrug or polymorph thereof as claimed in any one of claims 1 to 6, wherein L1表示C(O)、C2-6亚烯基、可选取代的C1-5亚烷基、-CH＝、可选取代的C6-10亚芳基-C1-5亚烷基-*、或N(Rc1)，其中Rc1表示H或C1-3烷基，符号*表示与基团X1的连接点，其中所述C1-5亚烷基和所述C6-10亚芳基-C1-5亚烷基各自独立地可选地被1-10个选自D、可选地氘代的C1-4烷基、羟基、氨基、巯基、卤素、氰基、C1-4烷氧基、C1-4烷基-NH-、卤代C1-4烷基、NH2-C1-4亚烷基-、C1-4烷基-NHC(O)-、C1-4烷基-C(O)NH-、和其任意组合的取代基取代，或L1表示-C(RL1RL2)-，其中RL1、RL2连同它们连接的碳原子一起形成可选取代的C3-8亚环烷基，和/或L 1 represents C(O), C 2-6 alkenylene, optionally substituted C 1-5 alkylene, -CH=, optionally substituted C 6-10 arylene-C 1-5 alkylene-*, or N(R c1 ), wherein R c1 represents H or C 1-3 alkyl, the symbol * represents the point of connection to the group X 1 , wherein the C 1-5 alkylene and the C 6-10 arylene-C 1-5 alkylene are each independently optionally substituted by 1 to 10 substituents selected from D, optionally deuterated C 1-4 alkyl, hydroxy, amino, thiol, halogen, cyano, C 1-4 alkoxy, C 1-4 alkyl-NH-, halogenated C 1-4 alkyl, NH 2 -C 1-4 alkylene-, C 1-4 alkyl-NHC(O)-, C 1-4 alkyl-C(O)NH-, and any combination thereof, or L 1 represents -C(R L1 R L2 )-, wherein R L1 and R L2 together with the carbon atom to which they are attached form an optionally substituted C 3-8 cycloalkylene group, and/or X1表示可选取代的C3-20亚环烷基、可选取代的4-至20-元亚杂环基或可选取代的5-至20-元亚杂芳基，其中所述C3-20亚环烷基和所述4-至20-元亚杂环基各自独立地可选地被一或多个选自D、可选地氘代的C1-4烷基、羟基、氨基、巯基、卤素、氰基、氧代基、C1-4烷氧基、C1-4烷基-NH-、卤代C1-4烷基、NH2-C1-4亚烷基、C1-4烷基-NHC(O)-、C1-4烷基-C(O)NH-、和其任意组合的取代基取代，所述5-至20-元亚杂芳基可选地被一或多个选自D、可选地氘代的C1-4烷基、羟基、氨基、巯基、卤素、氰基、C1-4烷氧基、C1-4烷基-NH-、卤代C1-4烷基、NH2-C1-4亚烷基-、C1-4烷基-NHC(O)-、C1-4烷基-C(O)NH-、和其任意组合的取代基取代。 X1 represents an optionally substituted C3-20 cycloalkylene, an optionally substituted 4- to 20-membered heterocyclylene or an optionally substituted 5- to 20-membered heteroarylene, wherein the C3-20 cycloalkylene and the 4- to 20-membered heterocyclylene are each independently optionally substituted by one or more substituents selected from D, optionally deuterated C1-4 alkyl, hydroxy, amino, thiol, halogen, cyano, oxo, C1-4 alkoxy, C1-4 alkyl-NH-, halogenated C1-4 alkyl, NH2- C1-4 alkylene, C1-4 alkyl-NHC(O)-, C1-4 alkyl-C(O)NH-, and any combination thereof, and the 5- to 20-membered heteroarylene is optionally substituted by one or more substituents selected from D, optionally deuterated C1-4 alkyl, hydroxy, amino, thiol, halogen, cyano, C1-4 alkoxy, C1-4 alkyl-NH-, halogenated C1-4 alkyl, NH2-C1-4 alkylene, C1-4 alkyl-NHC(O)-, C1-4 alkyl-C(O)NH-, and any combination thereof The group may be substituted with C 1-4 alkyl-NH-, halogenated C 1-4 alkyl, NH 2 -C 1-4 alkylene-, C 1-4 alkyl-NHC(O)-, C 1-4 alkyl-C(O)NH-, or any combination thereof. 如权利要求7所述的式(I)化合物或其盐、对映异构体、非对映异构体、同位素富集类似物、溶剂化物、前药或多晶型物，其中The compound of formula (I) or its salt, enantiomer, diastereomer, isotopically enriched analog, solvate, prodrug or polymorph as claimed in claim 7, wherein L1表示C(O)、亚乙烯基、可选取代的C1-5亚烷基、-CH＝、可选取代的亚苯基-C1-5亚烷基-*、可选取代的亚萘基-C1-5亚烷基-*、或N(Rc1)，其中Rc1表示H或C1-3烷基，符号*表示与基团X1的连接点，其中所述C1-5亚烷基、所述亚苯基-C1-5亚烷基和所述亚萘基-C1-5亚烷 基各自独立地可选地被1-10个选自D、可选地氘代的C1-4烷基、羟基、氨基、巯基、卤素、氰基、C1-4烷氧基、C1-4烷基-NH-、卤代C1-4烷基、NH2-C1-4亚烷基-、C1-4烷基-NHC(O)-、C1-4烷基-C(O)NH-、和其任意组合的取代基取代，或L1表示-C(RL1RL2)-，其中RL1、RL2连同它们连接的碳原子一起形成可选取代的C3-8亚环烷基，其中所述C3-8亚环烷基可选地被1-10个选自D、可选地氘代的C1-4烷基、羟基、氨基、巯基、卤素、氰基、C1-4烷氧基、C1-4烷基-NH-、卤代C1-4烷基、NH2-C1-4亚烷基-、C1-4烷基-NHC(O)-、C1-4烷基-C(O)NH-、和其任意组合的取代基取代，和/或L 1 represents C(O), vinylene, optionally substituted C 1-5 alkylene, -CH=, optionally substituted phenylene-C 1-5 alkylene-*, optionally substituted naphthylene-C 1-5 alkylene-*, or N(R c1 ), wherein R c1 represents H or C 1-3 alkyl, the symbol * represents the point of attachment to the group X 1 , wherein the C 1-5 alkylene, the phenylene-C 1-5 alkylene and the naphthylene-C 1-5 alkylene are each independently optionally substituted by 1 to 10 substituents selected from D, optionally deuterated C 1-4 alkyl, hydroxy, amino, thiol, halogen, cyano, C 1-4 alkoxy, C 1-4 alkyl-NH-, halogenated C 1-4 alkyl, NH 2 -C 1-4 alkylene-, C 1-4 alkyl-NHC(O)-, C 1-4 alkyl-C(O)NH-, and any combination thereof, or L 1 represents -C( RL1RL2 )-, wherein RL1 , RL2 together with the carbon atom to which they are attached form an optionally substituted C3-8 cycloalkylene group, wherein the C3-8 cycloalkylene group is optionally substituted with 1-10 substituents selected from D, optionally deuterated C1-4 alkyl , hydroxy, amino, mercapto , halogen, cyano, C1-4 alkoxy, C1-4 alkyl-NH-, halogenated C1-4 alkyl, NH2- C1-4 alkylene-, C1-4 alkyl-NHC(O)-, C1-4 alkyl-C(O)NH-, and any combination thereof, and/or X1表示以下二价基团： X1 represents the following divalent group: 亚环丙基、亚环丁基、亚环戊基、亚环戊烯基、亚环己基、亚环己烯基、亚环庚基、亚环辛基、亚十氢萘基、八氢并环戊二烯亚基、八氢-1H-茚亚基、螺[3.3]庚烷亚基、螺[2.5]辛烷亚基、螺[3.5]壬烷亚基、螺[4.4]壬烷亚基、螺[4.5]癸烷亚基、螺[5.5]十一烷亚基、对薄荷烷亚基、间薄荷烷亚基、亚奎宁环基、亚金刚烷基、亚降金刚烷基、亚冰片基、二环[2.2.1]庚烷亚基、2-氧代二环[2.2.1]庚烷亚基或二环[2.2.1]庚烯亚基，其可选地被一或多个选自D、可选地氘代的C1-4烷基、羟基、氨基、巯基、卤素、氰基、氧代基、C1-4烷氧基、C1-4烷基-NH-、卤代C1-4烷基、NH2-C1-4亚烷基-、C1-4烷基-NHC(O)-、C1-4烷基-C(O)NH-、和其任意组合的取代基取代；或cyclopropylene, cyclobutylene, cyclopentylidene, cyclopentenylidene, cyclohexylidene, cyclohexenylidene, cycloheptylene, cyclooctylene, decahydronaphthylene, octahydropentalenylidene, octahydro-1H-indenylidene, spiro[3.3]heptanylidene, spiro[2.5]octanylidene, spiro[3.5]nonaneylidene, spiro[4.4]nonaneylidene, spiro[4.5]decaneylidene, spiro[5.5]undecaneylidene, p-menthanylidene, m-menthanylidene, quinuclidinylidene, adamantylene, noradamantylene, bornylene, bicyclo[2.2.1]heptanylidene, 2-oxobicyclo[2.2.1]heptanylidene or bicyclo[2.2.1]heptenylidene, which may be optionally substituted with one or more radicals selected from D, optionally deuterated C or substituted by C 1-4 alkyl, hydroxy, amino, mercapto, halogen, cyano, oxo, C 1-4 alkoxy, C 1-4 alkyl-NH-, halogenated C 1-4 alkyl, NH 2 -C 1-4 alkylene-, C 1-4 alkyl-NHC(O)-, C 1-4 alkyl-C(O)NH-, and any combination thereof; or 亚氮杂环丁基、亚吡咯烷基、亚咪唑烷基、亚吡唑烷基、亚噁唑烷基、亚噻唑烷基、亚哌啶基、亚哌嗪基、亚吗啉基、亚硫代吗啉基、氮杂环庚烷亚基、氮杂环辛烷亚基、二氮杂环庚烷亚基、二氮杂环辛烷亚基、3-氮杂双环[3.1.0]己烷亚基、3-氮杂双环[3.1.1]庚烷亚基、2-氮杂双环[2.2.1]庚烷亚基、6-氮杂双环[3.1.1]庚烷亚基、2-氮杂双环[2.2.2]辛烷亚基、2,5-二氮杂双环[2.2.1]庚烷亚基、3,6-二氮杂双环[3.1.1]庚烷亚基、3-氮杂双环[3.2.1]辛烷亚基、3,8-二氮杂双环[3.2.1]辛烷亚基、2,5-二氮杂双环[2.2.2]辛烷亚基、2,6-二氮杂螺[3.3]庚烷亚基、2,7-二氮杂螺[3.5]壬烷亚基、3-氮杂螺[5.5]十一烷亚基、7-氮杂螺[3.5]壬烷亚基、或八氢吡咯并[3,4-c]吡咯亚基，其可选地被一或多个选自D、可选地氘代的C1-4烷基、羟基、氨基、巯基、卤素、氰基、氧代基、C1-4烷氧基、C1-4烷基-NH-、卤代C1-4烷基、NH2-C1-4亚烷基-、C1-4烷基-NHC(O)-、C1-4烷基-C(O)NH-、和其任意组合的取代基取代；或Azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanylidene, azacyclooctanylidene, diazacycloheptanylidene, diazacyclooctanylidene, 3-azabicyclo[3.1.0]hexanylidene, 3-azabicyclo[3.1.1]heptanylidene, 2-azabicyclo[2.2.1]heptanylidene, 6-azabicyclo[3.1.1]heptanylidene, 2-azabicyclo[2.2.2]octanylidene, 2,5-diazabicyclo[2. 2.1] heptanediyl, 3,6-diazabicyclo[3.1.1] heptanediyl, 3-azabicyclo[3.2.1] octandiyl, 3,8-diazabicyclo[3.2.1] octandiyl, 2,5-diazabicyclo[2.2.2] octandiyl, 2,6-diazaspiro[3.3] heptanediyl, 2,7-diazaspiro[3.5] nonanediyl, 3-azaspiro[5.5] undecanediyl, 7-azaspiro[3.5] nonanediyl, or octahydropyrrolo[3,4-c] pyrrolediyl, which is optionally substituted with one or more selected from D, optionally deuterated C or substituted by C 1-4 alkyl, hydroxy, amino, mercapto, halogen, cyano, oxo, C 1-4 alkoxy, C 1-4 alkyl-NH-, halogenated C 1-4 alkyl, NH 2 -C 1-4 alkylene-, C 1-4 alkyl-NHC(O)-, C 1-4 alkyl-C(O)NH-, and any combination thereof; or 亚呋喃基、亚噁唑基、亚异噁唑基、亚噁二唑基、亚噻吩基、亚噻唑基、亚异噻唑基、亚噻二唑基、亚吡咯基、亚咪唑基、亚吡唑基、亚三唑基、亚吡啶基、亚嘧啶基、亚哒嗪基、亚吡嗪基、亚吲哚基、亚异吲哚基、亚苯并呋喃基、亚异苯并呋喃基、亚苯并噻吩基、亚吲唑基、亚苯并咪唑基、亚苯并噁唑基、亚苯并异噁唑基、亚苯并噻唑基、亚苯并异噻唑基、亚苯并三唑基、亚苯并[2,1,3]噁二唑基、亚苯并[2,1,3]噻二唑基、亚苯并[1,2,3]噻二唑基、亚喹啉基、亚异喹啉基、亚萘啶基、亚噌啉基、亚喹唑啉基、亚喹喔啉基、亚酞嗪基、吡唑并[1,5-a]吡啶亚基、吡唑并[1,5-a]嘧啶亚基、咪唑并[1,2-a]吡啶亚基、1H-吡咯并[3,2-b]吡啶亚基、1H-吡咯并[2,3-b]吡啶亚 基、4H-氟[3,2-b]吡咯亚基、吡咯并[2,1-b]噻唑亚基或咪唑并[2,1-b]噻唑亚基，其可选地被一或多个选自D、可选地氘代的C1-4烷基、羟基、氨基、巯基、卤素、氰基、C1-4烷氧基、C1-4烷基-NH-、卤代C1-4烷基、NH2-C1-4亚烷基-、C1-4烷基-NHC(O)-、C1-4烷基-C(O)NH-、和其任意组合的取代基取代。furanylene, oxazolylene, isoxazolylene, oxadiazolylene, thienylene, thiazolylene, isothiazolylene, thiadiazolylene, pyrrolylene, imidazolylene, pyrazolylene, triazolylene, pyridylene, pyrimidylene, pyridazinylene, pyrazinylene, indolylene, isoindolylene, benzofuranylene, isobenzofuranylene, benzothienylene, indazolylene, benzimidazolylene, benzoxazolylene, benzisoxazolylene, benzothiazolylene, benzisothiazolylene, benzotriazole yl, benzo[2,1,3]oxadiazolyl, benzo[2,1,3]thiadiazolyl, benzo[1,2,3]thiadiazolyl, quinolyl, isoquinolyl, naphthyridyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-a]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl yl, 4H-fluoro[3,2-b]pyrroleyl, pyrrolo[2,1-b]thiazolyl or imidazo[2,1-b]thiazolyl, which is optionally substituted with one or more substituents selected from D, optionally deuterated C 1-4 alkyl, hydroxyl, amino, thiol, halogen, cyano, C 1-4 alkoxy, C 1-4 alkyl-NH-, halogenated C 1-4 alkyl, NH 2 -C 1-4 alkylene-, C 1-4 alkyl-NHC(O)-, C 1-4 alkyl-C(O)NH-, and any combination thereof. 如权利要求7所述的式(I)化合物或其盐、对映异构体、非对映异构体、同位素富集类似物、溶剂化物、前药或多晶型物，其中The compound of formula (I) or its salt, enantiomer, diastereomer, isotopically enriched analog, solvate, prodrug or polymorph as claimed in claim 7, wherein X1表示以下二价基团： X1 represents the following divalent group: 其中符号#表示与基团L1的连接点。The symbol # represents the point of connection to the group L1 . 如权利要求7所述的式(I)化合物或其盐、对映异构体、非对映异构体、同位素富集类似物、溶剂化物、前药或多晶型物，其中L1表示以下基团：The compound of formula (I) or its salt, enantiomer, diastereomer, isotopically enriched analog, solvate, prodrug or polymorph as claimed in claim 7, wherein L 1 represents the following group: C(O)、-CH2-、-(CH2)2-、-(CH2)3-、-CH(OH)-、-CHF2-、-CH2F-、NH、-CH＝CH-、-CH＝、或可选取代的亚苯基-CH2-*，其中符号*表示与基团X1的连接点，其中所述亚苯基可选地被1-4个选自D、可选地氘代的C1-4烷基、羟基、氨基、巯基、卤素、氰基、C1-4烷氧基、C1-4烷基-NH-、卤代C1-4烷基、NH2-C1-4亚烷基-、C1-4烷基-NHC(O)-、C1-4烷基-C(O)NH-、和其任意组合的取代基取代，或C(O), -CH2- , -( CH2 ) 2- , -( CH2 ) 3-, -CH(OH)-, -CHF2- , -CH2F- , NH, -CH=CH-, -CH=, or optionally substituted phenylene- CH2- *, wherein the symbol * represents the point of attachment to the group X1 , wherein the phenylene is optionally substituted with 1-4 substituents selected from D, optionally deuterated C1-4 alkyl, hydroxy, amino, mercapto, halogen, cyano, C1-4 alkoxy, C1-4 alkyl-NH-, halogenated C1-4 alkyl , NH2-C1-4 alkylene-, C1-4 alkyl-NHC(O)-, C1-4 alkyl - C ( O)NH-, and any combination thereof, or L1表示-C(RL1RL2)-，其中RL1、RL2连同它们连接的碳原子一起形成可选取代的亚环丙基、可选取代的亚环丁基、可选取代的亚环戊基、可选取代的亚环己基、可选取代的亚环庚 基、或可选取代的亚环辛基，其中所述亚环丙基、亚环丁基、亚环戊基、亚环己基、亚环庚基、或亚环辛基可选地被1-10个选自D、可选地氘代的C1-4烷基、羟基、氨基、巯基、卤素、氰基、C1-4烷氧基、C1-4烷基-NH-、卤代C1-4烷基、NH2-C1-4亚烷基-、C1-4烷基-NHC(O)-、C1-4烷基-C(O)NH-、和其任意组合的取代基取代。 L1 represents -C( RL1RL2 )-, wherein RL1 , RL2 together with the carbon atom to which they are attached form an optionally substituted cyclopropylene, optionally substituted cyclobutylene, optionally substituted cyclopentylene, optionally substituted cyclohexylene, optionally substituted cycloheptylene, or optionally substituted cyclooctylene, wherein the cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, or cyclooctylene are optionally substituted with 1-10 substituents selected from D, optionally deuterated C1-4 alkyl, hydroxy, amino, thiol, halogen, cyano, C1-4 alkoxy, C1-4 alkyl-NH-, halogenated C1-4 alkyl , NH2-C1-4 alkylene-, C1-4 alkyl-NHC(O)-, C1-4 alkyl - C ( O)NH-, and any combination thereof. 如权利要求1-6中任一项所述的式(I)化合物或其盐、对映异构体、非对映异构体、同位素富集类似物、溶剂化物、前药或多晶型物，其中L1表示键，且X1表示可选取代的5-至20-元含氮亚桥杂环基，其中所述5-至20-元含氮亚桥杂环基可选地被一或多个选自D、可选地氘代的C1-4烷基、羟基、氨基、巯基、卤素、氰基、氧代基、C1-4烷氧基、C1-4烷基-NH-、卤代C1-4烷基、NH2-C1-4亚烷基-、C1-4烷基-NHC(O)-、C1-4烷基-C(O)NH-、和其任意组合的取代基取代。A compound of formula (I) or a salt, enantiomer, diastereomer, isotopically enriched analog, solvate, prodrug or polymorph thereof as described in any one of claims 1 to 6, wherein L 1 represents a bond, and X 1 represents an optionally substituted 5- to 20-membered nitrogen-containing subbridged heterocyclic group, wherein the 5- to 20-membered nitrogen-containing subbridged heterocyclic group is optionally substituted with one or more substituents selected from D, optionally deuterated C 1-4 alkyl, hydroxyl, amino, thiol, halogen, cyano, oxo, C 1-4 alkoxy, C 1-4 alkyl-NH-, halogenated C 1-4 alkyl, NH 2 -C 1-4 alkylene-, C 1-4 alkyl-NHC(O)-, C 1-4 alkyl-C(O)NH-, and any combination thereof. 如权利要求11所述的式(I)化合物或其盐、对映异构体、非对映异构体、同位素富集类似物、溶剂化物、前药或多晶型物，其中X1表示以下二价基团：The compound of formula (I) or its salt, enantiomer, diastereomer, isotopically enriched analog, solvate, prodrug or polymorph as claimed in claim 11, wherein X1 represents the following divalent group: 3-氮杂双环[3.1.0]己烷亚基、3-氮杂双环[3.1.1]庚烷亚基、2-氮杂双环[2.2.1]庚烷亚基、6-氮杂双环[3.1.1]庚烷亚基、2-氮杂双环[2.2.2]辛烷亚基、2,5-二氮杂双环[2.2.1]庚烷亚基、3,6-二氮杂双环[3.1.1]庚烷亚基、3-氮杂双环[3.2.1]辛烷亚基、3,8-二氮杂双环[3.2.1]辛烷亚基、或2,5-二氮杂双环[2.2.2]辛烷亚基，其中所述二价基团可选地被一或多个选自D、可选地氘代的C1-4烷基、羟基、氨基、巯基、卤素、氰基、氧代基、C1-4烷氧基、C1-4烷基-NH-、卤代C1-4烷基、NH2-C1-4亚烷基-、C1-4烷基-NHC(O)-、C1-4烷基-C(O)NH-、和其任意组合的取代基取代。3-azabicyclo[3.1.0]hexanediyl, 3-azabicyclo[3.1.1]heptanylidene, 2-azabicyclo[2.2.1]heptanylidene, 6-azabicyclo[3.1.1]heptanylidene, 2-azabicyclo[2.2.2]octanylidene, 2,5-diazabicyclo[2.2.1]heptanylidene, 3,6-diazabicyclo[3.1.1]heptanylidene, 3-azabicyclo[3.2.1]octanylidene, 3,8-diazabicyclo[3.2.1]octanylidene, or 2,5-diazabicyclo[2.2.2]octanylidene, wherein the divalent radical is optionally substituted with one or more radicals selected from D, optionally deuterated C 1-4 alkyl, hydroxy, amino, thiol, halogen, cyano, oxo, C 1-4 alkoxy, C 1-4 alkyl ... The group may be substituted with C 1-4 alkyl-NH-, halogenated C 1-4 alkyl, NH 2 -C 1-4 alkylene-, C 1-4 alkyl-NHC(O)-, C 1-4 alkyl-C(O)NH-, or any combination thereof. 如权利要求11所述的式(I)化合物或其盐、对映异构体、非对映异构体、同位素富集类似物、溶剂化物、前药或多晶型物，其中The compound of formula (I) or its salt, enantiomer, diastereomer, isotopically enriched analog, solvate, prodrug or polymorph as claimed in claim 11, wherein X1表示以下二价基团： X1 represents the following divalent group: 其中符号#表示与基团L1的连接点。The symbol # represents the point of connection to the group L1 . 如权利要求1-13中任一项所述的式(I)化合物或其盐、对映异构体、非对映异构体、同位素富集类似物、溶剂化物、前药或多晶型物，其中X2表示C(O)、可选取代的C1-5亚烷基、可选取代的C3-8亚环烷基、可选取代的C1-2亚烷基-N(Rc2)-、-N(Rc2)-可选取代的C1-2亚烷基、或N(Rc3)，其中Rc2和Rc3各自独立地表示H或C1-3烷基，其中所述C1-5亚烷基和C3-8亚环烷基各自独立地可选地被1-10个选自D、可选地氘代的C1-4烷基、羟基、氨基、巯基、卤素、氰基、氧代基、C1-4烷氧基、C3-8环烷基、C1-4烷基-NH-、卤代C1-4烷基、NH2-C1-4亚烷基、C1-4烷基-NHC(O)-、C1-4烷基-C(O)NH-、和其任意组合的取代基取代，所述C1-2亚烷基可选地被1-4个选自D、可选地氘代的C1-4烷基、羟基、氨基、巯基、卤素、氰基、氧代基、C1-4烷氧基、C3-8环烷基、C1-4烷基-NH-、卤代C1-4烷基、NH2-C1-4亚烷基、C1-4烷基-NHC(O)-、C1-4烷基-C(O)NH-、和其任意组合的取代基取代。A compound of formula (I) or a salt, enantiomer, diastereomer, isotopically enriched analog, solvate, prodrug or polymorph thereof as described in any one of claims 1 to 13, wherein X 2 represents C(O), optionally substituted C 1-5 alkylene, optionally substituted C 3-8 cycloalkylene, optionally substituted C 1-2 alkylene-N(R c2 )-, -N(R c2 )-optionally substituted C 1-2 alkylene, or N(R c3 ), wherein R c2 and R c3 each independently represent H or C 1-3 alkyl, wherein the C 1-5 alkylene and C 3-8 cycloalkylene are each independently optionally substituted by 1-10 groups selected from D, optionally deuterated C 1-4 alkyl, hydroxyl, amino, thiol, halogen, cyano, oxo, C 1-4 alkoxy, C 3-8 cycloalkyl, C 1-4 alkyl-NH-, halogenated C 1-4 alkyl, NH 2 -C 1-4 alkylene, C 1-4 alkyl-NHC(O)-, C 1-4 alkyl-C(O)NH-, and any combination thereof, wherein the C 1-2 alkylene is optionally substituted with 1-4 substituents selected from D, optionally deuterated C 1-4 alkyl, hydroxy, amino, thiol, halogen, cyano, oxo, C 1-4 alkoxy, C 3-8 cycloalkyl, C 1-4 alkyl-NH-, halogenated C 1-4 alkyl, NH 2 -C 1-4 alkylene, C 1-4 alkyl-NHC(O)-, C 1-4 alkyl-C(O)NH-, and any combination thereof. 如权利要求14所述的式(I)化合物或其盐、对映异构体、非对映异构体、同位素富集类似物、溶剂化物、前药或多晶型物，其中X2表示C(O)、-CH2-、-(CH2)2-、-(CH2)3-、NH、-CH2-NH-、-(CH2)2-NH-、-NH-(CH2)2-、或-NH-CH2-。A compound of formula (I) or a salt, enantiomer, diastereomer, isotopically enriched analog, solvate, prodrug or polymorph thereof as claimed in claim 14, wherein X2 represents C(O), -CH2- , -( CH2 ) 2- , -( CH2 ) 3- , NH, -CH2 -NH-, -( CH2 ) 2 -NH-, -NH-( CH2 ) 2- , or -NH- CH2- . 如权利要求1-10中任一项所述的式(I)化合物或其盐、对映异构体、非对映异构体、同位素富集类似物、溶剂化物、前药或多晶型物，其中X2表示键，且其中当X2表示键时，L1不为键。A compound of formula (I) or a salt, enantiomer, diastereomer, isotopically enriched analog, solvate, prodrug or polymorph thereof as described in any one of claims 1 to 10, wherein X 2 represents a bond, and wherein when X 2 represents a bond, L 1 is not a bond. 如权利要求1-16中任一项所述的式(I)化合物或其盐、对映异构体、非对映异构体、同位素富集类似物、溶剂化物、前药或多晶型物，其中Ra1表示以下结构： A compound of formula (I) or a salt, enantiomer, diastereomer, isotopically enriched analog, solvate, prodrug or polymorph thereof as described in any one of claims 1 to 16, wherein R a1 represents the following structure: 其中in 环A表示4-至20-元亚杂环基、C3-20亚环烷基、C6-20亚芳基、或5-至20-元亚杂芳基，(Rd1)m1表示环A可选地被m1个基团Rd1取代，m1表示0至10的整数，各Rd1独立地表示氘、羟基、氨基、巯基、卤素、氰基、氧代基、可选氘代的C1-6烷基、可选氘代的C3-6环烷基、可选氘代的C1-6烷氧基、卤代C1-6烷基、C1-4烷基-NH-、C1-4烷基-NHC(O)-、C1-4烷基-C(O)NH-、或NH2-C1-6亚烷基-；和/或Ring A represents a 4- to 20-membered heterocyclylene group, a C 3-20 cycloalkylene group, a C 6-20 arylene group, or a 5- to 20-membered heteroarylene group, (R d1 ) m1 represents that Ring A is optionally substituted by m1 groups R d1 , m1 represents an integer from 0 to 10, and each R d1 independently represents deuterium, hydroxyl, amino, mercapto, halogen, cyano, oxo, optionally deuterated C 1-6 alkyl, optionally deuterated C 3-6 cycloalkyl, optionally deuterated C 1-6 alkoxy, halogenated C 1-6 alkyl, C 1-4 alkyl-NH-, C 1-4 alkyl-NHC(O)-, C 1-4 alkyl-C(O)NH-, or NH 2 -C 1-6 alkylene-; and/or 环B表示C6-20芳基、C3-20环烷基、4-至20-元杂环基、或5-至20-元杂芳基，(Rd2)m2表示环B可选地被m2个基团Rd2取代，m2表示0至10的整数，各Rd2独立地表示氘、羟基、氨基、巯基、卤素、氰基、氧代基、可选氘代的C1-6烷基、可选氘代的C3-6环烷基、可选氘代的C1-6烷氧基、卤代C1-6烷基、C1-4烷基-NH-、C1-4烷基-NHC(O)-、C1-4烷基-C(O)NH-、或NH2-C1-6亚烷基-。Ring B represents a C 6-20 aryl group, a C 3-20 cycloalkyl group, a 4- to 20-membered heterocyclyl group, or a 5- to 20-membered heteroaryl group, (R d2 ) m2 represents that Ring B is optionally substituted by m2 groups R d2 , m2 represents an integer from 0 to 10, and each R d2 independently represents deuterium, hydroxyl, amino, thiol, halogen, cyano, oxo, optionally deuterated C 1-6 alkyl, optionally deuterated C 3-6 cycloalkyl, optionally deuterated C 1-6 alkoxy, halogenated C 1-6 alkyl, C 1-4 alkyl-NH—, C 1-4 alkyl-NHC(O)—, C 1-4 alkyl-C(O)NH—, or NH 2 -C 1-6 alkylene-. 如权利要求17所述的式(I)化合物或其盐、对映异构体、非对映异构体、同位素富集类似物、溶剂化物、前药或多晶型物，其中环A表示以下二价基团：The compound of formula (I) or its salt, enantiomer, diastereomer, isotopically enriched analog, solvate, prodrug or polymorph as claimed in claim 17, wherein ring A represents the following divalent group: 亚环丙基、亚环丁基、亚环戊基、亚环戊烯基、亚环己基、亚环己烯基、亚环庚基、亚环庚烯基、亚环辛基、亚十氢萘基、八氢并环戊二烯亚基、八氢-1H-茚亚基、螺[3.3]庚烷亚基、螺[2.5]辛烷亚基、螺[3.5]壬烷亚基、螺[4.4]壬烷亚基、螺[4.5]癸烷亚基、螺[5.5]十一烷亚基、对薄荷烷亚基、间薄荷烷亚基、亚奎宁环基、亚金刚烷基、亚降金刚烷基、亚冰片基、二环[2.2.1]庚烷亚基、2-氧代二环[2.2.1]庚烷亚基或二环[2.2.1]庚烯亚基，其可选地被一或多个选自D、羟基、氨基、巯基、卤素、氰基、氧代基、可选氘代的C1-6烷基、可选氘代的C3-6环烷基、可选氘代的C1-6烷氧基、卤代C1-6烷基、C1-4烷基-NH-、C1-4烷基-NHC(O)-、C1-4烷基-C(O)NH-、NH2-C1-6亚烷基-、和其任意组合的取代基取代；Cyclopropylene, cyclobutylene, cyclopentylidene, cyclopentenylidene, cyclohexylidene, cyclohexenylidene, cycloheptylidene, cycloheptenylidene, cyclooctylene, decahydronaphthylene, octahydropentalenylidene, octahydro-1H-indenylidene, spiro[3.3]heptanylidene, spiro[2.5]octanylidene, spiro[3.5]nonaneylidene, spiro[4.4]nonaneylidene, spiro[4.5]decaneylidene, spiro[ 5.5] undecanediyl, p-menthanylidene, m-menthanylidene, quinuclidinyl, adamantylene, noradamantylene, bornylene, bicyclo[2.2.1]heptanylidene, 2-oxobicyclo[2.2.1]heptanylidene or bicyclo[2.2.1]heptenylidene, which is optionally substituted with one or more substituents selected from D, hydroxy, amino, thiol, halogen, cyano, oxo, optionally deuterated C 1-6 alkyl, optionally deuterated C 3-6 cycloalkyl, optionally deuterated C 1-6 alkoxy, halogenated C 1-6 alkyl, C 1-4 alkyl-NH-, C 1-4 alkyl-NHC(O)-, C 1-4 alkyl-C(O)NH-, NH 2 -C 1-6 alkylene-, and any combination thereof; 亚苯基或亚萘基，其可选地被一或多个选自D、羟基、氨基、巯基、卤素、氰基、可选氘代的C1-6烷基、可选氘代的C3-6环烷基、可选氘代的C1-6烷氧基、卤代C1-6烷基、C1-4烷基-NH-、C1-4烷基-NHC(O)-、C1-4烷基-C(O)NH-、NH2-C1-6亚烷基-、和其任意组合的取代基取代；Phenylene or naphthylene, which is optionally substituted with one or more substituents selected from D, hydroxy, amino, mercapto, halogen, cyano, optionally deuterated C 1-6 alkyl, optionally deuterated C 3-6 cycloalkyl, optionally deuterated C 1-6 alkoxy , halogenated C 1-6 alkyl, C 1-4 alkyl-NH-, C 1-4 alkyl-NHC(O)-, C 1-4 alkyl-C(O)NH-, NH 2 -C 1-6 alkylene-, and any combination thereof; 亚氮杂环丁基、亚吡咯烷基、亚咪唑烷基、亚吡唑烷基、亚噁唑烷基、亚噻唑烷基、亚哌啶基、亚哌嗪基、亚吗啉基、亚硫代吗啉基、亚吡喃基、亚二氢吡喃基、氮杂环庚烷亚基、氮杂环辛烷亚基、二氮杂环庚烷亚基、二氮杂环辛烷亚基、3-氮杂双环[3.1.0]己烷亚基、3-氮杂双环[3.1.1]庚烷亚基、2-氮杂双环[2.2.1]庚烷亚基、6-氮杂双环[3.1.1]庚烷亚基、2-氮杂双环[2.2.2]辛烷亚基、2,5-二氮杂双环[2.2.1]庚烷亚基、3,6-二氮杂双环[3.1.1]庚烷亚基、3-氮杂双环[3.2.1]辛烷亚基、3,8-二氮杂双环[3.2.1]辛烷亚基、2,5-二氮 杂双环[2.2.2]辛烷亚基、2,6-二氮杂螺[3.3]庚烷亚基、2,7-二氮杂螺[3.5]壬烷亚基、3-氮杂螺[5.5]十一烷亚基、7-氮杂螺[3.5]壬烷亚基或八氢吡咯并[3,4-c]吡咯亚基，其可选地被一或多个选自D、羟基、氨基、巯基、卤素、氰基、氧代基、可选氘代的C1-6烷基、可选氘代的C3-6环烷基、可选氘代的C1-6烷氧基、卤代C1-6烷基、C1-4烷基-NH-、C1-4烷基-NHC(O)-、C1-4烷基-C(O)NH-、NH2-C1-6亚烷基-、和其任意组合的取代基取代；或aziridinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyranyl, dihydropyranyl, azepanyl, azocyclooctanyl, diazepanyl, diazacyclooctanyl, 3-azabicyclo[3.1.0]hexaneyl, 3-azabicyclo[3.1.1]heptanyl, 2-azabicyclo[2.2.1]heptanediyl, 6-azabicyclo[3.1.1]heptanediyl, 2-azabicyclo[2.2.2]octanadiyl, 2,5-diazabicyclo[2.2.1]heptanediyl, 3,6-diazabicyclo[3.1.1]heptanediyl, 3-azabicyclo[3.2.1]octanadiyl, 3,8-diazabicyclo[3.2.1]octanadiyl, 2,5-diazabicyclo[2.2.1]heptanediyl, heterobicyclo[2.2.2]octanylene, 2,6-diazaspiro[3.3]heptylene, 2,7-diazaspiro[3.5]nonanylene, 3-azaspiro[5.5]undecylene, 7-azaspiro[3.5]nonanylene or octahydropyrrolo[3,4-c]pyrroleylene, which is optionally substituted with one or more substituents selected from D, hydroxy, amino, thiol, halogen, cyano, oxo, optionally deuterated C 1-6 alkyl, optionally deuterated C 3-6 cycloalkyl, optionally deuterated C 1-6 alkoxy, halogenated C 1-6 alkyl, C 1-4 alkyl-NH-, C 1-4 alkyl-NHC(O)-, C 1-4 alkyl-C(O)NH-, NH 2 -C 1-6 alkylene-, and any combination thereof; or 亚呋喃基、亚噁唑基、亚异噁唑基、亚噁二唑基、亚噻吩基、亚噻唑基、亚异噻唑基、亚噻二唑基、亚吡咯基、亚咪唑基、亚吡唑基、亚三唑基、亚吡啶基、亚嘧啶基、亚哒嗪基、亚吡嗪基、亚吲哚基、亚异吲哚基、亚苯并呋喃基、亚异苯并呋喃基、亚苯并噻吩基、亚吲唑基、亚苯并咪唑基、亚苯并噁唑基、亚苯并异噁唑基、亚苯并噻唑基、亚苯并异噻唑基、亚苯并三唑基、亚苯并[2,1,3]噁二唑基、亚苯并[2,1,3]噻二唑基、亚苯并[1,2,3]噻二唑基、亚喹啉基、亚异喹啉基、亚萘啶基、亚噌啉基、亚喹唑啉基、亚喹喔啉基、亚酞嗪基、吡唑并[1,5-a]吡啶亚基、吡唑并[1,5-a]嘧啶亚基、咪唑并[1,2-a]吡啶亚基、1H-吡咯并[3,2-b]吡啶亚基、1H-吡咯并[2,3-b]吡啶亚基、4H-氟[3,2-b]吡咯亚基、吡咯并[2,1-b]噻唑亚基或咪唑并[2,1-b]噻唑亚基，其可选地被一或多个选自D、羟基、氨基、巯基、卤素、氰基、可选氘代的C1-6烷基、可选氘代的C3-6环烷基、可选氘代的C1- 6烷氧基、卤代C1-6烷基、C1-4烷基-NH-、C1-4烷基-NHC(O)-、C1-4烷基-C(O)NH-、NH2-C1-6亚烷基-、和其任意组合的取代基取代；furanylene, oxazolylene, isoxazolylene, oxadiazolylene, thienylene, thiazolylene, isothiazolylene, thiadiazolylene, pyrrolylene, imidazolylene, pyrazolylene, triazolylene, pyridylene, pyrimidylene, pyridazinylene, pyrazinylene, indolylene, isoindolylene, benzofuranylene, isobenzofuranylene, benzothienylene, indazolylene, benzimidazolylene, benzoxazolylene, benzisoxazolylene, benzothiazolylene, benzisothiazolylene, benzotriazolylene, benzo[2,1,3]oxadiazolylene, benzo[2,1,3]thiadiazolylene, benzo[1,2,3 ] thiadiazolyl, quinolyl, isoquinolyl, naphthyridyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-a]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, 4H-fluoro[3,2-b]pyrrole, pyrrolo[2,1-b]thiazolyl or imidazo[2,1-b]thiazolyl, which is optionally substituted with one or more selected from D, hydroxy, amino, thiol, halogen, cyano, optionally deuterated C The substituents are optionally substituted with C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, C 1-4 alkyl-NH-, C 1-4 alkyl-NHC(O)-, C 1-4 alkyl-C(O)NH-, NH 2 -C 1-6 alkylene-, and any combination thereof; 和/或and / or 环B表示以下基团：Ring B represents the following group: 环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环庚基、环辛基、十氢萘基、八氢并环戊二烯基、八氢-1H-茚基、螺[3.3]庚烷基、螺[2.5]辛烷基、螺[3.5]壬烷基、螺[4.4]壬烷基、螺[4.5]癸烷基、螺[5.5]十一烷基、对薄荷烷基、间薄荷烷基、奎宁环基、金刚烷基、降金刚烷基、冰片基、二环[2.2.1]庚烷基、2-氧代二环[2.2.1]庚烷基或二环[2.2.1]庚烯基，其可选地被一或多个选自D、羟基、氨基、巯基、卤素、氰基、氧代基、可选氘代的C1-6烷基、可选氘代的C3-6环烷基、可选氘代的C1-6烷氧基、卤代C1-6烷基、C1-4烷基-NH-、C1-4烷基-NHC(O)-、C1-4烷基-C(O)NH-、NH2-C1-6亚烷基-、和其任意组合的取代基取代；cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, decahydronaphthyl, octahydropentalenyl, octahydro-1H-indenyl, spiro[3.3]heptyl, spiro[2.5]octanyl, spiro[3.5]nonanyl, spiro[4.4]nonanyl, spiro[4.5]decyl, spiro[5.5]undecyl, p-menthanyl, m-menthanyl, quinuclidinyl, adamantyl, noradamantyl, bornyl, bicyclo[2.2.1]heptyl, 2-oxobicyclo[2.2.1]heptyl or bicyclo[2.2.1]heptenyl, which may be optionally substituted with one or more alkyl radicals selected from D, hydroxy, amino, thiol, halogen, cyano, oxo, optionally deuterated C 1-6 alkyl, optionally deuterated C 3-6 cycloalkyl, optionally deuterated C 1-6 alkoxy, halogenated C 3-6 alkyl, halogenated C 1-6 alkoxy, alkyl radicals selected from D, hydroxy, amino, thiol, halogenated C 3-6 cycloalkyl, alkyl radicals selected from D, hydroxy, amino, thiol, halogenated C 3-6 cycloalkyl, alkyl radicals selected from D, hydroxy, amino, thiol, halogenated C 1-6 alkyl, alkyl radicals selected from D, hydroxy, amino, thiol, halogenated C 3-6 cycloalkyl, alkyl radicals selected from D, hydroxy, amino, thiol, halogenated C 1-6 alkoxy, halogenated C substituted by C 1-6 alkyl, C 1-4 alkyl-NH-, C 1-4 alkyl-NHC(O)-, C 1-4 alkyl-C(O)NH-, NH 2 -C 1-6 alkylene-, and any combination thereof; 苯基或萘基，其可选地被一或多个选自D、羟基、氨基、巯基、卤素、氰基、可选氘代的C1-6烷基、可选氘代的C3-6环烷基、可选氘代的C1-6烷氧基、卤代C1-6烷基、C1-4烷基-NH-、C1-4烷基-NHC(O)-、C1-4烷基-C(O)NH-、NH2-C1-6亚烷基-、和其任意组合的取代基取代；Phenyl or naphthyl, which is optionally substituted with one or more substituents selected from D, hydroxy, amino, mercapto, halogen, cyano, optionally deuterated C 1-6 alkyl, optionally deuterated C 3-6 cycloalkyl, optionally deuterated C 1-6 alkoxy, halogenated C 1-6 alkyl , C 1-4 alkyl-NH-, C 1-4 alkyl-NHC(O)-, C 1-4 alkyl-C(O)NH-, NH 2 -C 1-6 alkylene-, and any combination thereof; 氮杂环丁基、吡咯烷基、咪唑烷基、吡唑烷基、噁唑烷基、噻唑烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、氮杂环庚烷基、氮杂环辛烷基、二氮杂环庚烷基、二氮杂环辛烷基、3-氮杂双环[3.1.0]己烷基、3-氮杂双环[3.1.1]庚烷基、2-氮杂双环[2.2.1]庚烷基、6-氮杂双环[3.1.1]庚烷基、2-氮杂双环[2.2.2]辛烷基、2,5-二氮杂双环[2.2.1]庚烷基、3,6-二氮 杂双环[3.1.1]庚烷基、3-氮杂双环[3.2.1]辛烷基、3,8-二氮杂双环[3.2.1]辛烷基、2,5-二氮杂双环[2.2.2]辛烷基、2,6-二氮杂螺[3.3]庚烷基、2,7-二氮杂螺[3.5]壬烷基、3-氮杂螺[5.5]十一烷基、7-氮杂螺[3.5]壬烷基或八氢吡咯并[3,4-c]吡咯基，其可选地被一或多个选自D、羟基、氨基、巯基、卤素、氰基、氧代基、可选氘代的C1-6烷基、可选氘代的C3-6环烷基、可选氘代的C1-6烷氧基、卤代C1-6烷基、C1-4烷基-NH-、C1-4烷基-NHC(O)-、azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, azocanyl, diazacycloheptyl, diazaoctanyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.1]heptanyl, 2-azabicyclo[2.2.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 2-azabicyclo[2.2.2]octanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3,6-diaza ...2]octanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3,6-diazabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.1]heptanyl, 2-azabicyclo[2.2.1]heptanyl, 3,6-diazabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.1]heptanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 3,6-diaza heterobicyclo[3.1.1]heptyl, 3-azabicyclo[3.2.1]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, 2,5-diazabicyclo[2.2.2]octanyl, 2,6-diazaspiro[3.3]heptyl, 2,7-diazaspiro[3.5]nonyl, 3-azaspiro[5.5]undecyl, 7-azaspiro[3.5]nonyl or octahydropyrrolo[3,4-c]pyrrolyl, which is optionally substituted by one or more selected from D, hydroxy, amino, thiol, halogen, cyano, oxo, optionally deuterated C 1-6 alkyl, optionally deuterated C 3-6 cycloalkyl, optionally deuterated C 1-6 alkoxy, halogenated C 1-6 alkyl, C 1-4 alkyl-NH-, C 1-4 alkyl-NHC(O)-, C1-4烷基-C(O)NH-、NH2-C1-6亚烷基-、和其任意组合的取代基取代；或C 1-4 alkyl-C(O)NH-, NH 2 -C 1-6 alkylene-, and any combination thereof; or 呋喃基、噁唑基、异噁唑基、噁二唑基、噻吩基、噻唑基、异噻唑基、噻二唑基、吡咯基、咪唑基、吡唑基、三唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、吲哚基、异吲哚基、苯并呋喃基、异苯并呋喃基、苯并噻吩基、吲唑基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噻唑基、苯并异噻唑基、苯并三唑基、苯并[2,1,3]噁二唑基、苯并[2,1,3]噻二唑基、苯并[1,2,3]噻二唑基、喹啉基、异喹啉基、萘啶基、噌啉基、喹唑啉基、喹喔啉基、酞嗪基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-a]吡啶基、1H-吡咯并[3,2-b]吡啶基、1H-吡咯并[2,3-b]吡啶基、4H-氟[3,2-b]吡咯基、吡咯并[2,1-b]噻唑基或咪唑并[2,1-b]噻唑基，其可选地被一或多个选自D、羟基、氨基、巯基、卤素、氰基、可选氘代的C1-6烷基、可选氘代的C3-6环烷基、可选氘代的C1-6烷氧基、卤代C1-6烷基、C1-4烷基-NH-、C1-4烷基-NHC(O)-、C1-4烷基-C(O)NH-、NH2-C1-6亚烷基-、和其任意组合的取代基取代。furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, benzo[2,1,3]oxadiazolyl, benzo[2,1,3]thiadiazolyl, benzo[1,2,3]thiadiazolyl, quinoline , 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, 4H-fluoro[3,2-b]pyrrolyl, pyrrolo[2,1-b]thiazolyl or imidazo[2,1-b]thiazolyl, which may be substituted with one or more radicals selected from D, hydroxy, amino, thiol, halogen, cyano, optionally deuterated C The group may be substituted with C 1-6 alkyl, optionally deuterated C 3-6 cycloalkyl, optionally deuterated C 1-6 alkoxy, halogenated C 1-6 alkyl, C 1-4 alkyl-NH-, C 1-4 alkyl-NHC(O)-, C 1-4 alkyl-C(O)NH-, NH 2 -C 1-6 alkylene-, and any combination thereof. 如权利要求17所述的式(I)化合物或其盐、对映异构体、非对映异构体、同位素富集类似物、溶剂化物、前药或多晶型物，其中环A表示以下二价基团： The compound of formula (I) or its salt, enantiomer, diastereomer, isotopically enriched analog, solvate, prodrug or polymorph as claimed in claim 17, wherein ring A represents the following divalent group: 其中符号**表示与环B的连接点；The symbol ** indicates the connection point with ring B; 和/或and / or 环B表示以下基团： Ring B represents the following group: 如权利要求1-17中任一项所述的式(I)化合物或其盐、对映异构体、非对映异构体、同位素富集类似物、溶剂化物、前药或多晶型物，其中Ra1表示以下结构： A compound of formula (I) or a salt, enantiomer, diastereomer, isotopically enriched analog, solvate, prodrug or polymorph thereof as described in any one of claims 1 to 17, wherein R a1 represents the following structure: 如权利要求1-17中任一项所述的式(I)化合物或其盐、对映异构体、非对映异构体、同位素富集类似物、溶剂化物、前药或多晶型物，其中-X1-X2-Ra1表示以下结构： The compound of formula (I) or a salt, enantiomer, diastereomer, isotopically enriched analog, solvate, prodrug or polymorph thereof according to any one of claims 1 to 17, wherein -X 1 -X 2 -R a1 represents the following structure: 如权利要求1所述的式(I)化合物或其盐、对映异构体、非对映异构体、同位素富集类似物、溶剂化物、前药或多晶型物，其选自：The compound of formula (I) or its salt, enantiomer, diastereomer, isotopically enriched analog, solvate, prodrug or polymorph as claimed in claim 1, which is selected from: 3-(5-((4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)甲基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)甲基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)甲基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(4-((4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(6-((4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(6-((4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(7-((4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(7-((4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(2-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)乙基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(2-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(3-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)丙基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(3-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)氟甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)fluoromethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)二氟甲基)-1-氧代 异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)difluoromethyl)-1-oxo isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(1-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)环丙基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(1-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)cyclopropyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(1-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)环丁基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(1-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)cyclobutyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(1-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)环戊基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(1-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)cyclopentyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((2-(4-氯苯基)环戊-1-烯-1-基)甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((2-(4-chlorophenyl)cyclopent-1-en-1-yl)methyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((2-(4-氯苯基)环庚-1-烯-1-基)甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((2-(4-chlorophenyl)cyclohept-1-en-1-yl)methyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((2-(4-氯苯基)环丙基)甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((2-(4-chlorophenyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((2-(4-氯苯基)环丁基)甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((2-(4-chlorophenyl)cyclobutyl)methyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4,4-二甲基-2-(噻吩-2-基)环己-1-烯-1-基)甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4,4-dimethyl-2-(thiophen-2-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((2-(呋喃-2-基)-4,4-二甲基环己-1-烯-1-基)甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((2-(furan-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4,4-二甲基-2-(噻唑-5-基)环己-1-烯-1-基)甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4,4-dimethyl-2-(thiazol-5-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4,4-二甲基-2-(噁唑-5-基)环己-1-烯-1-基)甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4,4-dimethyl-2-(oxazol-5-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)氨基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)amino)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌啶-4-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((1-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperidin-4-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌啶-4-基)氨基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((1-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)氮杂环丁烷-3-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((1-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)azetidin-3-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)氮杂环丁烷-3-基亚基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((1-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)azetidin-3-ylidene)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3-羟基氮杂环丁烷-3-基)(羟基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((1-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3-hydroxyazetidin-3-yl)(hydroxy)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)甲基)苯基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮； 3-(5-(4-((4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)methyl)phenyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)氨基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2-氧代哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2-oxopiperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((3-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)咪唑烷-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((3-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)imidazolidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-1,4-二氮杂环庚烷-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,4-diazepan-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((6-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,6-二氮杂螺[3.3]庚烷-2-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((6-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((7-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,7-二氮杂螺[3.5]壬烷-2-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((7-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((5-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((5-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(8-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(8-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(3-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(3-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((3-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((3-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((6-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((6-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((1R,5S)-6-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(((1R,5S)-6-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((3-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((3-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((8-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((8-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((5-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((5-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,5-diazabicyclo[2.2.2]octan-2-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((1R,4R)-5-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(((1R,4R)-5-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2-(氟甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2-(fluoromethyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,5-二甲基哌嗪-1-基)甲基)- 1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,5-dimethylpiperazin-1-yl)methyl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2-(三氟甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2-(trifluoromethyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,3-二甲基哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,3-dimethylpiperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((3-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((3-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((6-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)甲基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((6-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((3-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((3-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((8-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)甲基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((8-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((5-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)甲基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((5-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,5-diazabicyclo[2.2.2]octan-2-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((1R,4R)-5-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(((1R,4R)-5-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2-(氟甲基)哌嗪-1-基)甲基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2-(fluoromethyl)piperazin-1-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,5-二甲基哌嗪-1-基)甲基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,5-dimethylpiperazin-1-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2-(三氟甲基)哌嗪-1-基)甲基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2-(trifluoromethyl)piperazin-1-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,3-二甲基哌嗪-1-基)甲基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,3-dimethylpiperazin-1-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((3-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((3-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((6-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)甲基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((6-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((3-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((3-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((8-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)甲基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((8-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((5-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)甲基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮； 3-(5-((5-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,5-diazabicyclo[2.2.2]octan-2-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2-(氟甲基)哌嗪-1-基)甲基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2-(fluoromethyl)piperazin-1-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,5-二甲基哌嗪-1-基)甲基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,5-dimethylpiperazin-1-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2-(三氟甲基)哌嗪-1-基)甲基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2-(trifluoromethyl)piperazin-1-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,3-二甲基哌嗪-1-基)甲基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,3-dimethylpiperazin-1-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((3-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((3-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((6-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)甲基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((6-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((3-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((3-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((8-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)甲基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((8-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((5-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)甲基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((5-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,5-diazabicyclo[2.2.2]octan-2-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2-(氟甲基)哌嗪-1-基)甲基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2-(fluoromethyl)piperazin-1-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,5-二甲基哌嗪-1-基)甲基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,5-dimethylpiperazin-1-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2-(三氟甲基)哌嗪-1-基)甲基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2-(trifluoromethyl)piperazin-1-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,3-二甲基哌嗪-1-基)甲基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,3-dimethylpiperazin-1-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((3-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2-氧代咪唑烷-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((3-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2-oxoimidazolidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((3-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2-氧代咪唑烷-1-基)甲基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((3-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2-oxoimidazolidin-1-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((3-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2-氧代咪唑烷-1-基)甲基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((3-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2-oxoimidazolidin-1-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((3-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2-氧代咪唑烷-1-基)甲基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((3-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2-oxoimidazolidin-1-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((3-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2-氧代咪唑烷-1-基)甲基)-1- 氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(4-((3-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2-oxoimidazolidin-1-yl)methyl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4-(4-氯苯基)-6,6-二甲基-5,6-二氢-2H-吡喃-3-基)甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)哌嗪-1-基)甲基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)哌嗪-1-基)甲基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)哌嗪-1-基)甲基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((4-(4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(4-((4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)哌嗪-1-基)氨基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((1-(4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)哌啶-4-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((1-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperidin-4-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((1-(4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)哌啶-4-基)氨基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((1-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((1-(4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)氮杂环丁烷-3-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((1-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)azetidin-3-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((1-(4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)氮杂环丁烷-3-基亚基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((1-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)azetidin-3-ylene)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((1-(4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)-3-羟基氮杂环丁烷-3-基)(羟基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((1-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)-3-hydroxyazetidin-3-yl)(hydroxy)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((3-(4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)咪唑烷-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((3-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)imidazolidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)-1,4-二氮杂环庚烷-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)-1,4-diazepan-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((7-(4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)-2,7-二氮杂螺[3.5]壬烷-2-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((7-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((6-(4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)-2,6-二氮杂螺[3.3]庚烷-2-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((6-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((5-(4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮； 3-(5-((5-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((4-(4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)哌嗪-1-基)甲基)苯基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(4-((4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)methyl)phenyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((3-(4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((3-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((6-(4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((6-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((3-(4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((3-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((8-(4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((8-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((5-(4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((5-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)-2,5-diazabicyclo[2.2.2]octan-2-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((1R,4R)-5-(4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(((1R,4R)-5-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)-2-(氟甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)-2-(fluoromethyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)-3,5-二甲基哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)-2-(三氟甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)-2-(trifluoromethyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)-3,3-二甲基哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-羰基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-carbonyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-羰基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-羰基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(3-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)咪唑烷-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(3-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)imidazolidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-1,4-二氮杂环庚烷-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,4-diazepane-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(7-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,7-二氮杂螺[3.5]壬烷-2-羰 基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(7-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(6-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,6-二氮杂螺[3.3]庚烷-2-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(6-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(5-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)八氢吡咯并[3,4-c]吡咯-2-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(5-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(3-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(3-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-6-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(6-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(6-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(3-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(3-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(8-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(8-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(5-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(5-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,5-diazabicyclo[2.2.2]octane-2-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((1R,4R)-5-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((1R,4R)-5-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2-(氟甲基)哌嗪-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2-(fluoromethyl)piperazine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,5-二甲基哌嗪-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,5-dimethylpiperazine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2-(三氟甲基)哌嗪-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2-(trifluoromethyl)piperazine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,3-二甲基哌嗪-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,3-dimethylpiperazine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(3-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)咪唑烷-1-羰基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(3-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)imidazolidine-1-carbonyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-1,4-二氮杂环庚烷-1-羰基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,4-diazepane-1-carbonyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(7-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,7-二氮杂螺[3.5]壬烷-2-羰基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(7-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(6-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,6-二氮杂螺[3.3]庚烷-2-羰基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(6-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(5-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)八氢吡咯并[3,4-c]吡咯-2-羰基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮； 3-(5-(5-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(3-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-羰基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(3-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-6-carbonyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(6-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-羰基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(6-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-carbonyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(3-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-羰基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(3-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(8-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-羰基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(8-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(5-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-羰基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(5-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,5-diazabicyclo[2.2.2]octane-2-carbonyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2-(氟甲基)哌嗪-1-羰基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2-(fluoromethyl)piperazine-1-carbonyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,5-二甲基哌嗪-1-羰基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,5-dimethylpiperazine-1-carbonyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2-(三氟甲基)哌嗪-1-羰基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2-(trifluoromethyl)piperazine-1-carbonyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,3-二甲基哌嗪-1-羰基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,3-dimethylpiperazine-1-carbonyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(3-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)咪唑烷-1-羰基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(3-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)imidazolidine-1-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-1,4-二氮杂环庚烷-1-羰基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,4-diazepane-1-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(7-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,7-二氮杂螺[3.5]壬烷-2-羰基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(7-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(6-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,6-二氮杂螺[3.3]庚烷-2-羰基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(6-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(5-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)八氢吡咯并[3,4-c]吡咯-2-羰基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(5-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(3-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-羰基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(3-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-6-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(6-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-羰基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(6-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(3-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-羰基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(3-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(8-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3- 羰基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(8-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octane-3- carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(5-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-羰基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(5-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,5-diazabicyclo[2.2.2]octane-2-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(6-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-羰基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(6-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2-(氟甲基)哌嗪-1-羰基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2-(fluoromethyl)piperazine-1-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,5-二甲基哌嗪-1-羰基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,5-dimethylpiperazine-1-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2-(三氟甲基)哌嗪-1-羰基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2-(trifluoromethyl)piperazine-1-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,3-二甲基哌嗪-1-羰基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,3-dimethylpiperazine-1-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(3-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)咪唑烷-1-羰基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(3-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)imidazolidine-1-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-1,4-二氮杂环庚烷-1-羰基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,4-diazepane-1-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(7-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,7-二氮杂螺[3.5]壬烷-2-羰基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(7-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(6-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,6-二氮杂螺[3.3]庚烷-2-羰基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(6-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(5-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)八氢吡咯并[3,4-c]吡咯-2-羰基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(5-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(3-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-羰基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(3-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-6-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(6-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-羰基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(6-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(3-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-羰基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(3-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(8-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-羰基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(8-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(5-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-羰基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(5-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,5-diazabicyclo[2.2.2]octane-2-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(6-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-羰基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮； 3-(5-(6-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2-(氟甲基)哌嗪-1-羰基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2-(fluoromethyl)piperazine-1-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,5-二甲基哌嗪-1-羰基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,5-dimethylpiperazine-1-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2-(三氟甲基)哌嗪-1-羰基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2-(trifluoromethyl)piperazine-1-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,3-二甲基哌嗪-1-羰基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,3-dimethylpiperazine-1-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氯-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氯-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)甲基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氯-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)甲基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氯-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)甲基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((4-((4'-氯-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(4-((4-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(2-(4-((4'-氯-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)乙基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(2-(4-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(3-(4-((4'-氯-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)丙基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(3-(4-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((1-((4'-氯-[1,1'-联苯]-2-基)甲基)哌啶-4-基)氨基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((1-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)piperidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氯-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)氨基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氟-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-fluoro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-氟-5-((4-((4'-氟-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(4-fluoro-5-((4-((4'-fluoro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(6-氟-5-((4-((4'-氟-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(6-fluoro-5-((4-((4'-fluoro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(7-氟-5-((4-((4'-氟-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(7-fluoro-5-((4-((4'-fluoro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((4-((4'-氟-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二 酮；3-(4-((4-((4'-fluoro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidin-2,6-dione; 3-(6-((4-((4'-氟-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(6-((4-((4'-fluoro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4'-氟-[1,1'-联苯]-2-羰基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-(4'-fluoro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氟-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-fluoro-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4'-氟-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-(4'-fluoro-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((3-(4'-氟-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((3-(4'-fluoro-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氯-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)氟甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)fluoromethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氯-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)二氟甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)difluoromethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(1-(4-((4'-氯-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)环丙基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(1-(4-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)cyclopropyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(1-(4-((4'-氯-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)环丁基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(1-(4-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)cyclobutyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(1-(4-((4'-氯-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)环戊基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(1-(4-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)cyclopentyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((2-(4-溴苯基)环戊-1-烯-1-基)甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((2-(4-bromophenyl)cyclopent-1-en-1-yl)methyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((2-(4-溴苯基)环庚-1-烯-1-基)甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((2-(4-bromophenyl)cyclohept-1-en-1-yl)methyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((2-(4-溴苯基)环丙基)甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((2-(4-bromophenyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((2-(4-溴苯基)环丁基)甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((2-(4-bromophenyl)cyclobutyl)methyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-氧代-5-((4-(2-(噻吩-2-基)苄基)哌嗪-1-基)甲基)异吲哚啉-2-基)哌啶-2,6-二酮；3-(1-oxo-5-((4-(2-(thiophen-2-yl)benzyl)piperazin-1-yl)methyl)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(2-(呋喃-2-基)苄基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-(2-(Furan-2-yl)benzyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(2-(1H-吡咯-2-基)苄基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-(2-(1H-pyrrol-2-yl)benzyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(2-(1-甲基-1H-吡咯-2-基)苄基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-(2-(1-methyl-1H-pyrrol-2-yl)benzyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(2-(1-甲基-1H-吡唑-5-基)苄基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-(2-(1-methyl-1H-pyrazol-5-yl)benzyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-氧代-5-((4-(2-(噻唑-5-基)苄基)哌嗪-1-基)甲基)异吲哚啉-2-基)哌啶-2,6-二酮；3-(1-oxo-5-((4-(2-(thiazol-5-yl)benzyl)piperazin-1-yl)methyl)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(2-(噁唑-5-基)苄基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮； 3-(5-((4-(2-(oxazol-5-yl)benzyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((1-((4'-氯-[1,1'-联苯]-2-基)甲基)-3-羟基氮杂环丁烷-3-基)(羟基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((1-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-3-hydroxyazetidin-3-yl)(hydroxy)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((1-((4'-氯-[1,1'-联苯]-2-基)甲基)氮杂环丁烷-3-基亚基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((1-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)azetidin-3-ylidene)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((1-((4'-氯-[1,1'-联苯]-2-基)甲基)氮杂环丁烷-3-基)氨基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((1-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)azetidin-3-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((1-((4'-氯-[1,1'-联苯]-2-基)甲基)氮杂环丁烷-3-基)氨基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((1-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)azetidin-3-yl)amino)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((1-((4'-氯-[1,1'-联苯]-2-基)甲基)氮杂环丁烷-3-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((1-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)azetidin-3-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((4-((4'-氯-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)甲基)苯基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(4-((4-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)methyl)phenyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氯-[1,1'-联苯]-2-基)氨基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-chloro-[1,1'-biphenyl]-2-yl)amino)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氯-[1,1'-联苯]-2-基)氨基)-3,3-二氟哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-chloro-[1,1'-biphenyl]-2-yl)amino)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((1-((4'-氯-[1,1'-联苯]-2-基)甲基)哌啶-4-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((1-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)piperidin-4-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((3-((4'-氯-[1,1'-联苯]-2-基)甲基)咪唑烷-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((3-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)imidazolidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氯-[1,1'-联苯]-2-基)甲基)-1,4-二氮杂环庚烷-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-1,4-diazepan-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氯-[1,1'-联苯]-2-基)甲基)-2-氧代哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-2-oxopiperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((7-((4'-氯-[1,1'-联苯]-2-基)甲基)-2,7-二氮杂螺[3.5]壬烷-2-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((7-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((6-((4'-氯-[1,1'-联苯]-2-基)甲基)-2,6-二氮杂螺[3.3]庚烷-2-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((6-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((5-((4'-氯-[1,1'-联苯]-2-基)甲基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((5-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4'-氯-[1,1'-联苯]-2-基)-1H-1,2,3-三氮唑-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-(4'-chloro-[1,1'-biphenyl]-2-yl)-1H-1,2,3-triazol-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((1-((4'-氯-[1,1'-联苯]-2-基)甲基)-3,3-二氟哌啶-4-基)氨基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((1-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-3,3-difluoropiperidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(3-((4'-氯-[1,1'-联苯]-2-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-1-氧代异吲哚啉-2-基) 哌啶-2,6-二酮；3-(5-(3-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-1-oxoisoindolin-2-yl) Piperidine-2,6-dione; 3-(5-((3-((4'-氯-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((3-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((3-((4'-氯-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((3-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((3-((4'-氯-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((3-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((3-((4'-氯-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((3-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((6-((4'-氯-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((6-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((3-((4'-氯-[1,1'-联苯]-2-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((3-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((8-((4'-氯-[1,1'-联苯]-2-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((8-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((5-((4'-氯-[1,1'-联苯]-2-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((5-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-2,5-diazabicyclo[2.2.2]octan-2-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((1R,4R)-5-((4'-氯-[1,1'-联苯]-2-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(((1R,4R)-5-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氯-[1,1'-联苯]-2-基)甲基)-2-(氟甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-2-(fluoromethyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氯-[1,1'-联苯]-2-基)甲基)-3,5-二甲基哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-3,5-dimethylpiperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氯-[1,1'-联苯]-2-基)甲基)-2-(三氟甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-2-(trifluoromethyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氯-[1,1'-联苯]-2-基)甲基)-3,3-二甲基哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-3,3-dimethylpiperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((3-((4'-氯-[1,1'-联苯]-2-基)甲基)-2-氧代咪唑烷-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((3-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-2-oxoimidazolidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((3-((4'-氯-[1,1'-联苯]-2-基)甲基)-2-氧代咪唑烷-1-基)甲基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((3-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-2-oxoimidazolidin-1-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((3-((4'-氯-[1,1'-联苯]-2-基)甲基)-2-氧代咪唑烷-1-基)甲基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((3-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-2-oxoimidazolidin-1-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((3-((4'-氯-[1,1'-联苯]-2-基)甲基)-2-氧代咪唑烷-1-基)甲基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮； 3-(5-((3-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-2-oxoimidazolidin-1-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((3-((4'-氯-[1,1'-联苯]-2-基)甲基)-2-氧代咪唑烷-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(4-((3-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-2-oxoimidazolidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((3-(4-氯苯基)吡啶-4-基)甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((3-(4-chlorophenyl)pyridin-4-yl)methyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4-(4-氯苯基)吡啶-3-基)甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4-(4-chlorophenyl)pyridin-3-yl)methyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((3-(4-氯苯基)吡啶-2-基)甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((3-(4-chlorophenyl)pyridin-2-yl)methyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(2-(5-氯吡啶-2-基)苄基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-(2-(5-chloropyridin-2-yl)benzyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氯-[1,1'-联苯]-3-基)甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-chloro-[1,1'-biphenyl]-3-yl)methyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(3-(5-氯吡啶-2-基)苄基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-(3-(5-chloropyridin-2-yl)benzyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-氧代-5-((4-(3-(噻吩-2-基)苄基)哌嗪-1-基)甲基)异吲哚啉-2-基)哌啶-2,6-二酮；3-(1-oxo-5-((4-(3-(thiophen-2-yl)benzyl)piperazin-1-yl)methyl)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(3-(呋喃-2-基)苄基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-(3-(Furan-2-yl)benzyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(3-(1H-吡咯-2-基)苄基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-(3-(1H-pyrrol-2-yl)benzyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氯-[1,1'-联苯]-4-基)甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-chloro-[1,1'-biphenyl]-4-yl)methyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4-(5-氯吡啶-2-基)苄基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-(4-(5-chloropyridin-2-yl)benzyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-氧代-5-((4-(4-(噻吩-2-基)苄基)哌嗪-1-基)甲基)异吲哚啉-2-基)哌啶-2,6-二酮；3-(1-oxo-5-((4-(4-(thiophen-2-yl)benzyl)piperazin-1-yl)methyl)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4-(呋喃-2-基)苄基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-(4-(Furan-2-yl)benzyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4-(1H-吡咯-2-基)苄基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-(4-(1H-pyrrol-2-yl)benzyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((6-(4-氯苯基)吡啶-3-基)甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((6-(4-chlorophenyl)pyridin-3-yl)methyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-([2,4'-联吡啶]-5-基甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-([2,4'-bipyridyl]-5-ylmethyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-氧代-5-((4-((5-苯基吡嗪-2-基)甲基)哌嗪-1-基)甲基)异吲哚啉-2-基)哌啶-2,6-二酮；3-(1-oxo-5-((4-((5-phenylpyrazin-2-yl)methyl)piperazin-1-yl)methyl)isoindolin-2-yl)piperidine-2,6-dione; 3-(1-氧代-5-((4-(2-苯基嘧啶-5-羰基)哌嗪-1-基)甲基)异吲哚啉-2-基)哌啶-2,6-二酮；3-(1-oxo-5-((4-(2-phenylpyrimidine-5-carbonyl)piperazin-1-yl)methyl)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((5-(4-氯苯基)噻吩-2-基)甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((5-(4-chlorophenyl)thiophen-2-yl)methyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-([2,2'-联噻吩]-5-基甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-([2,2'-bithiophene]-5-ylmethyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((5-(呋喃-2-基)噻吩-2-基)甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((5-(furan-2-yl)thiophen-2-yl)methyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((5-(4-氯苯基)呋喃-2-基)甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((5-(4-chlorophenyl)furan-2-yl)methyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-氧代-5-((4-((5-(噻吩-2-基)呋喃-2-基)甲基)哌嗪-1-基)甲基)异吲哚啉-2-基)哌啶-2,6-二酮； 3-(1-oxo-5-((4-((5-(thiophen-2-yl)furan-2-yl)methyl)piperazin-1-yl)methyl)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-([2,2'-联呋喃]-5-基甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-([2,2'-bifuran]-5-ylmethyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4'-氯-[1,1'-联苯]-2-羰基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-(4'-chloro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(3-(4-氯苯基)异烟酰基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-(3-(4-chlorophenyl)isonicotinyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4'-氯-[1,1'-联苯]-2-羰基)哌嗪-1-基)甲基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-(4'-chloro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4'-氯-[1,1'-联苯]-2-羰基)哌嗪-1-基)甲基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-(4'-chloro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4'-氯-[1,1'-联苯]-2-羰基)哌嗪-1-基)甲基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-(4'-chloro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((4-(4'-氯-[1,1'-联苯]-2-羰基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(4-((4-(4'-chloro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((1-(4'-氯-[1,1'-联苯]-2-羰基)哌啶-4-基)氨基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((1-(4'-chloro-[1,1'-biphenyl]-2-carbonyl)piperidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((1-(4'-氯-[1,1'-联苯]-2-羰基)哌啶-4-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((1-(4'-chloro-[1,1'-biphenyl]-2-carbonyl)piperidin-4-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((1-(4'-氯-[1,1'-联苯]-2-羰基)氮杂环丁烷-3-基)氨基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((1-(4'-chloro-[1,1'-biphenyl]-2-carbonyl)azetidin-3-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((1-(4'-氯-[1,1'-联苯]-2-羰基)氮杂环丁烷-3-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((1-(4'-chloro-[1,1'-biphenyl]-2-carbonyl)azetidin-3-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((1-(4'-氯-[1,1'-联苯]-2-羰基)-3-羟基氮杂环丁烷-3-基)(羟基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((1-(4'-chloro-[1,1'-biphenyl]-2-carbonyl)-3-hydroxyazetidin-3-yl)(hydroxy)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((1-(4'-氯-[1,1'-联苯]-2-羰基)氮杂环丁烷-3-基亚基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((1-(4'-chloro-[1,1'-biphenyl]-2-carbonyl)azetidin-3-ylidene)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((3-(4'-氯-[1,1'-联苯]-2-羰基)咪唑烷-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((3-(4'-chloro-[1,1'-biphenyl]-2-carbonyl)imidazolidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4'-氯-[1,1'-联苯]-2-羰基)-1,4-二氮杂环庚烷-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-(4'-chloro-[1,1'-biphenyl]-2-carbonyl)-1,4-diazepan-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((4-(4'-氯-[1,1'-联苯]-2-羰基)哌嗪-1-基)甲基)苯基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(4-((4-(4'-chloro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)methyl)phenyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((7-(4'-氯-[1,1'-联苯]-2-羰基)-2,7-二氮杂螺[3.5]壬烷-2-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((7-(4'-chloro-[1,1'-biphenyl]-2-carbonyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((6-(4'-氯-[1,1'-联苯]-2-羰基)-2,6-二氮杂螺[3.3]庚烷-2-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((6-(4'-chloro-[1,1'-biphenyl]-2-carbonyl)-2,6-diazaspiro[3.3]heptane-2-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((5-(4'-氯-[1,1'-联苯]-2-羰基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((5-(4'-chloro-[1,1'-biphenyl]-2-carbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(3-(4'-氯-[1,1'-联苯]-2-羰基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(3-(4'-chloro-[1,1'-biphenyl]-2-carbonyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((3-(4'-氯-[1,1'-联苯]-2-羰基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮； 3-(5-((3-(4'-chloro-[1,1'-biphenyl]-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((3-(4'-氯-[1,1'-联苯]-2-羰基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((3-(4'-chloro-[1,1'-biphenyl]-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((3-(4'-氯-[1,1'-联苯]-2-羰基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((3-(4'-chloro-[1,1'-biphenyl]-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((3-(4'-氯-[1,1'-联苯]-2-羰基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((3-(4'-chloro-[1,1'-biphenyl]-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((6-(4'-氯-[1,1'-联苯]-2-羰基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((6-(4'-chloro-[1,1'-biphenyl]-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((3-(4'-氯-[1,1'-联苯]-2-羰基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((3-(4'-chloro-[1,1'-biphenyl]-2-carbonyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((8-(4'-氯-[1,1'-联苯]-2-羰基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((8-(4'-chloro-[1,1'-biphenyl]-2-carbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((5-(4'-氯-[1,1'-联苯]-2-羰基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((5-(4'-chloro-[1,1'-biphenyl]-2-carbonyl)-2,5-diazabicyclo[2.2.2]octan-2-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((1R,4R)-5-(4'-氯-[1,1'-联苯]-2-羰基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(((1R,4R)-5-(4'-chloro-[1,1'-biphenyl]-2-carbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4'-氯-[1,1'-联苯]-2-羰基)-2-(氟甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-(4'-chloro-[1,1'-biphenyl]-2-carbonyl)-2-(fluoromethyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4'-氯-[1,1'-联苯]-2-羰基)-3,5-二甲基哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-(4'-chloro-[1,1'-biphenyl]-2-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4'-氯-[1,1'-联苯]-2-羰基)-2-(三氟甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-(4'-chloro-[1,1'-biphenyl]-2-carbonyl)-2-(trifluoromethyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4'-氯-[1,1'-联苯]-2-羰基)-3,3-二甲基哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-(4'-chloro-[1,1'-biphenyl]-2-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((4'-氯-[1,1'-联苯]-2-基)甲基)哌嗪-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(4-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((4'-氯-[1,1'-联苯]-2-基)甲基)哌嗪-1-羰基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(4-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-carbonyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((4'-氯-[1,1'-联苯]-2-基)甲基)哌嗪-1-羰基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(4-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((4'-氯-[1,1'-联苯]-2-基)甲基)哌嗪-1-羰基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(4-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-(4-((4'-氯-[1,1'-联苯]-2-基)甲基)哌嗪-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(4-(4-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((4'-氯-[1,1'-联苯]-2-基)氨基)哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(4-((4'-chloro-[1,1'-biphenyl]-2-yl)amino)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(3-((4'-氯-[1,1'-联苯]-2-基)甲基)咪唑烷-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(3-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)imidazolidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((4'-氯-[1,1'-联苯]-2-基)甲基)-1,4-二氮杂环庚烷-1-羰基)-1-氧代异吲哚啉-2-基)哌啶- 2,6-二酮；3-(5-(4-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-1,4-diazepane-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione; 3-(5-(7-((4'-氯-[1,1'-联苯]-2-基)甲基)-2,7-二氮杂螺[3.5]壬烷-2-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(7-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(6-((4'-氯-[1,1'-联苯]-2-基)甲基)-2,6-二氮杂螺[3.3]庚烷-2-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(6-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(5-((4'-氯-[1,1'-联苯]-2-基)甲基)八氢吡咯并[3,4-c]吡咯-2-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(5-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(3-((4'-氯-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(3-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-6-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(3-((4'-氯-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-羰基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(3-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-6-carbonyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(3-((4'-氯-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-羰基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(3-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-6-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(3-((4'-氯-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-羰基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(3-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-6-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(6-((4'-氯-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(6-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(3-((4'-氯-[1,1'-联苯]-2-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(3-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(8-((4'-氯-[1,1'-联苯]-2-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(8-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(5-((4'-氯-[1,1'-联苯]-2-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(5-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-2,5-diazabicyclo[2.2.2]octane-2-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((1R,4R)-5-((4'-氯-[1,1'-联苯]-2-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((1R,4R)-5-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((4'-氯-[1,1'-联苯]-2-基)甲基)-2-(氟甲基)哌嗪-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(4-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-2-(fluoromethyl)piperazine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((4'-氯-[1,1'-联苯]-2-基)甲基)-3,5-二甲基哌嗪-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(4-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-3,5-dimethylpiperazine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((4'-氯-[1,1'-联苯]-2-基)甲基)-2-(三氟甲基)哌嗪-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(4-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-2-(trifluoromethyl)piperazine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((4'-氯-[1,1'-联苯]-2-基)甲基)-3,3-二甲基哌嗪-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(4-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-3,3-dimethylpiperazine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮； 3-(5-((4-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-氟-5-((4-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(4-fluoro-5-((4-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(6-氟-5-((4-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(6-fluoro-5-((4-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(7-氟-5-((4-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(7-fluoro-5-((4-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((4-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(4-((4-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(6-((4-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(6-((4-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((1-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)氮杂环丁烷-3-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((1-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)azetidin-3-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((1-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)氮杂环丁烷-3-基亚基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((1-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)azetidin-3-ylidene)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((1-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3-羟基氮杂环丁烷-3-基)(羟基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((1-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3-hydroxyazetidin-3-yl)(hydroxy)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((1-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌啶-4-基)氨基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((1-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((1-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌啶-4-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((1-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperidin-4-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((4-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)甲基)苯基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(4-((4-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)methyl)phenyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((7-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,7-二氮杂螺[3.5]壬烷-2-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((7-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((6-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,6-二氮杂螺[3.3]庚烷-2-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((6-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((5-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((5-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((3-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((3-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((6-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((6-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((3-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((3-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((8-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3- 基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((8-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octane-3- yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((5-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((5-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,5-diazabicyclo[2.2.2]octan-2-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((1R,4R)-5-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(((1R,4R)-5-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2-(氟甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2-(fluoromethyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,5-二甲基哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,5-dimethylpiperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2-(三氟甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2-(trifluoromethyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,3-二甲基哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,3-dimethylpiperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((3-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2-氧代咪唑烷-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((3-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2-oxoimidazolidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-氟-5-((3-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2-氧代咪唑烷-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(4-fluoro-5-((3-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2-oxoimidazolidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(6-氟-5-((3-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2-氧代咪唑烷-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(6-fluoro-5-((3-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2-oxoimidazolidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(7-氟-5-((3-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2-氧代咪唑烷-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(7-fluoro-5-((3-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2-oxoimidazolidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((3-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2-氧代咪唑烷-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(4-((3-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2-oxoimidazolidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(8-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(8-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(3-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(3-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-(4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((1-(4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)哌啶-4-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((1-(4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperidin-4-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((1-(4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)氮杂环丁烷-3-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((1-(4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)azetidin-3-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((1-(4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)氮杂环丁烷-3-基亚基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮； 3-(5-((1-(4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)azetidin-3-ylene)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((1-(4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)-3-羟基氮杂环丁烷-3-基)(羟基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((1-(4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)-3-hydroxyazetidin-3-yl)(hydroxy)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((1-(4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)哌啶-4-基)氨基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((1-(4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((7-(4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)-2,7-二氮杂螺[3.5]壬烷-2-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((7-(4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((6-(4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)-2,6-二氮杂螺[3.3]庚烷-2-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((6-(4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)-2,6-diazaspiro[3.3]heptane-2-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((5-(4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((5-(4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((3-(4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((3-(4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((6-(4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((6-(4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((3-(4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((3-(4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((8-(4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((8-(4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((5-(4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((5-(4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)-2,5-diazabicyclo[2.2.2]octan-2-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((1R,4R)-5-(4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(((1R,4R)-5-(4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)-2-(氟甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-(4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)-2-(fluoromethyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)-3,5-二甲基哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-(4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)-2-(三氟甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-(4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)-2-(trifluoromethyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)-3,3-二甲基哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-(4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(8-(4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(8-(4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(3-(4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(3-(4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-羰基)-1-氧代异吲哚啉- 2-基)哌啶-2,6-二酮；3-(5-(4-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-carbonyl)-1-oxoisoindolin- 2-yl)piperidine-2,6-dione; 3-(5-(3-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)咪唑烷-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(3-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)imidazolidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-1,4-二氮杂环庚烷-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(4-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,4-diazepane-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(7-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,7-二氮杂螺[3.5]壬烷-2-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(7-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(6-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,6-二氮杂螺[3.3]庚烷-2-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(6-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(5-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)八氢吡咯并[3,4-c]吡咯-2-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(5-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(3-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(3-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-6-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(6-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(6-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(3-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(3-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(8-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(8-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(5-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(5-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,5-diazabicyclo[2.2.2]octane-2-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((1R,4R)-5-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((1R,4R)-5-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2-(氟甲基)哌嗪-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(4-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2-(fluoromethyl)piperazine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,5-二甲基哌嗪-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(4-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,5-dimethylpiperazine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2-(三氟甲基)哌嗪-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(4-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2-(trifluoromethyl)piperazine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,3-二甲基哌嗪-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(4-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,3-dimethylpiperazine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-氟-5-(3-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(4-fluoro-5-(3-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-6-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-氟-5-(6-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮； 3-(4-fluoro-5-(6-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-氟-5-(3-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(4-fluoro-5-(3-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-氟-5-(8-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(4-fluoro-5-(8-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-氟-5-(5-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(4-fluoro-5-(5-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,5-diazabicyclo[2.2.2]octane-2-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-氟-5-(4-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2-(氟甲基)哌嗪-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(4-fluoro-5-(4-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2-(fluoromethyl)piperazine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-氟-5-(4-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,5-二甲基哌嗪-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(4-fluoro-5-(4-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,5-dimethylpiperazine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-氟-5-(4-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2-(三氟甲基)哌嗪-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(4-fluoro-5-(4-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2-(trifluoromethyl)piperazine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-氟-5-(4-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,3-二甲基哌嗪-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(4-fluoro-5-(4-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,3-dimethylpiperazine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(6-氟-5-(3-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(6-fluoro-5-(3-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-6-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(6-氟-5-(3-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(6-fluoro-5-(3-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(6-氟-5-(5-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(6-fluoro-5-(5-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,5-diazabicyclo[2.2.2]octane-2-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(6-氟-5-(6-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(6-fluoro-5-(6-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(6-氟-5-(4-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,5-二甲基哌嗪-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(6-fluoro-5-(4-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,5-dimethylpiperazine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(6-氟-5-(4-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,3-二甲基哌嗪-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(6-fluoro-5-(4-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,3-dimethylpiperazine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(7-氟-5-(3-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(7-fluoro-5-(3-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-6-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(7-氟-5-(8-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(7-fluoro-5-(8-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(7-氟-5-(5-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(7-fluoro-5-(5-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,5-diazabicyclo[2.2.2]octane-2-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(7-氟-5-(4-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,5-二甲基哌嗪-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(7-fluoro-5-(4-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,5-dimethylpiperazine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(7-氟-5-(4-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,3-二甲基哌嗪-1-羰基)- 1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(7-fluoro-5-(4-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,3-dimethylpiperazine-1-carbonyl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-氧代-5-((4-((4',5,5-三甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)甲基)异吲哚啉-2-基)哌啶-2,6-二酮；3-(1-oxo-5-((4-((4',5,5-trimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)methyl)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氨基-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-amino-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4-(4-氯苯基)-5,6-二氢-2H-吡喃-3-基)甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4-(4-chlorophenyl)-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4-(4-氟苯基)-5,6-二氢-2H-吡喃-3-基)甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4-(4-fluorophenyl)-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氯-4,4-二氟-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-chloro-4,4-difluoro-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氯-4-甲氧基-4-甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-chloro-4-methoxy-4-methyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((8-(4-氯苯基)螺[4.5]癸-7-烯-7-基)甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((8-(4-chlorophenyl)spiro[4.5]dec-7-en-7-yl)methyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((6-(4-氯苯基)螺[3.5]壬-6-烯-7-基)甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((4'-氨基-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(4-((4'-amino-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((4'-氟-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(4-((4'-fluoro-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((4-(4-氯苯基)-5,6-二氢-2H-吡喃-3-基)甲基)哌嗪-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(4-((4-(4-chlorophenyl)-5,6-dihydro-2H-pyran-3-yl)methyl)piperazine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((4-(4-氟苯基)-5,6-二氢-2H-吡喃-3-基)甲基)哌嗪-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(4-((4-(4-fluorophenyl)-5,6-dihydro-2H-pyran-3-yl)methyl)piperazine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((4'-氯-4,4-二氟-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(4-((4'-chloro-4,4-difluoro-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((4'-氯-4-甲氧基-4-甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(4-((4'-chloro-4-methoxy-4-methyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((4-(4-氯苯基)-6,6-二甲基-5,6-二氢-2H-吡喃-3-基)甲基)哌嗪-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)piperazine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((8-(4-氯苯基)螺[4.5]癸-7-烯-7-基)甲基)哌嗪-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(4-((8-(4-chlorophenyl)spiro[4.5]dec-7-en-7-yl)methyl)piperazine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((6-(4-氯苯基)螺[3.5]壬-6-烯-7-基)甲基)哌嗪-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮； 3-(5-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 5-((4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)甲基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-((4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-((4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)甲基)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮；5-((4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione; 5-((4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)甲基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮；5-((4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione; 6-((4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)甲基)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮；6-((4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione; 4-((4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)甲基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；4-((4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-((4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)氨基)哌啶-1-基)甲基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-((4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)amino)piperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-((4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2-氧代哌嗪-1-基)甲基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-((4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2-oxopiperazin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-((3-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)咪唑烷-1-基)甲基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-((3-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)imidazolidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-((4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-1,4-二氮杂环庚烷-1-基)甲基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-((4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,4-diazepan-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-((7-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,7-二氮杂螺[3.5]壬烷-2-基)甲基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-((7-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-((6-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,6-二氮杂螺[3.3]庚烷-2-基)甲基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-((6-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-((5-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)甲基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-((5-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-((3-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-((3-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-((6-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)甲基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-((6-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-((3-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-((3-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-((8-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)甲基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-((8-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-((5-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)甲基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-((5-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,5-diazabicyclo[2.2.2]octan-2-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(((1R,4R)-5-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,5-二氮杂双环[2.2.1] 庚烷-2-基)甲基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-(((1R,4R)-5-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,5-diazabicyclo[2.2.1] heptane-2-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-((4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2-(氟甲基)哌嗪-1-基)甲基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-((4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2-(fluoromethyl)piperazin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-((4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,5-二甲基哌嗪-1-基)甲基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-((4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,5-dimethylpiperazin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-((4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2-(三氟甲基)哌嗪-1-基)甲基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-((4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2-(trifluoromethyl)piperazin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-((4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,3-二甲基哌嗪-1-基)甲基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-((4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,3-dimethylpiperazin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-((3-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2-氧代咪唑烷-1-基)甲基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-((3-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2-oxoimidazolidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 2-(2,6-二氧代哌啶-3-基)-5-((4-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)甲基)异吲哚啉-1,3-二酮；2-(2,6-dioxopiperidin-3-yl)-5-((4-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)methyl)isoindoline-1,3-dione; 5-((4-((4'-氯-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)甲基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-((4-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-((4-((4'-氯-[1,1'-联苯]-3-基)甲基)哌嗪-1-基)甲基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-((4-((4'-chloro-[1,1'-biphenyl]-3-yl)methyl)piperazin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-((4-((4'-氯-[1,1'-联苯]-4-基)甲基)哌嗪-1-基)甲基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-((4-((4'-chloro-[1,1'-biphenyl]-4-yl)methyl)piperazin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-((4-((3-(4-氯苯基)吡啶-4-基)甲基)哌嗪-1-基)甲基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-((4-((3-(4-chlorophenyl)pyridin-4-yl)methyl)piperazin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-((4-([2,4'-联吡啶]-5-基甲基)哌嗪-1-基)甲基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-((4-([2,4'-bipyridyl]-5-ylmethyl)piperazin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 2-(2,6-二氧代哌啶-3-基)-5-((4-((5-苯基吡嗪-2-基)甲基)哌嗪-1-基)甲基)异吲哚啉-1,3-二酮；2-(2,6-dioxopiperidin-3-yl)-5-((4-((5-phenylpyrazin-2-yl)methyl)piperazin-1-yl)methyl)isoindoline-1,3-dione; 5-((4-((5-(4-氯苯基)噻吩-2-基)甲基)哌嗪-1-基)甲基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-((4-((5-(4-chlorophenyl)thiophen-2-yl)methyl)piperazin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 2-(2,6-二氧代哌啶-3-基)-5-((4-((5-(噻吩-2-基)呋喃-2-基)甲基)哌嗪-1-基)甲基)异吲哚啉-1,3-二酮；2-(2,6-dioxopiperidin-3-yl)-5-((4-((5-(thiophen-2-yl)furan-2-yl)methyl)piperazin-1-yl)methyl)isoindoline-1,3-dione; 2-(2,6-二氧代哌啶-3-基)-5-((4-((4',5,5-三甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)甲基)异吲哚啉-1,3-二酮；2-(2,6-dioxopiperidin-3-yl)-5-((4-((4',5,5-trimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)methyl)isoindoline-1,3-dione; 5-((4-((4'-氨基-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)甲基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-((4-((4'-amino-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 2-(2,6-二氧代哌啶-3-基)-5-((4-((4'-氟-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)甲基)异吲哚啉-1,3-二酮；2-(2,6-dioxopiperidin-3-yl)-5-((4-((4'-fluoro-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)methyl)isoindoline-1,3-dione; 5-((4-((4-(4-氯苯基)-5,6-二氢-2H-吡喃-3-基)甲基)哌嗪-1-基)甲基)-2-(2,6-二氧代哌啶-3-基) 异吲哚啉-1,3-二酮；5-((4-((4-(4-chlorophenyl)-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl) Isoindoline-1,3-dione; 5-((4-((4'-氯-4,4-二氟-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)甲基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-((4-((4'-chloro-4,4-difluoro-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-((4-((4'-氯-4-甲氧基-4-甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)甲基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-((4-((4'-chloro-4-methoxy-4-methyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-((4-((4-(4-氯苯基)-6,6-二甲基-5,6-二氢-2H-吡喃-3-基)甲基)哌嗪-1-基)甲基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-((4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-((4-((8-(4-氯苯基)螺[4.5]癸-7-烯-7-基)甲基)哌嗪-1-基)甲基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-((4-((8-(4-chlorophenyl)spiro[4.5]dec-7-en-7-yl)methyl)piperazin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-((4-((6-(4-氯苯基)螺[3.5]壬-6-烯-7-基)甲基)哌嗪-1-基)甲基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-((4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-羰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-羰基)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮；5-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione; 5-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-羰基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮；5-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione; 6-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-羰基)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮；6-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione; 5-(3-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)咪唑烷-1-羰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-(3-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)imidazolidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-1,4-二氮杂环庚烷-1-羰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,4-diazepane-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(7-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,7-二氮杂螺[3.5]壬烷-2-羰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-(7-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(6-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,6-二氮杂螺[3.3]庚烷-2-羰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-(6-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(5-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)八氢吡咯并[3,4-c]吡咯-2-羰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-(5-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(3-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-羰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-(3-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-6-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(3-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-羰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-(3-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(6-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-羰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮； 5-(6-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(8-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-羰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-(8-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(5-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-羰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-(5-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,5-diazabicyclo[2.2.2]octane-2-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2-(氟甲基)哌嗪-1-羰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2-(fluoromethyl)piperazine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-((1R,4R)-5-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-羰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-((1R,4R)-5-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,5-二甲基哌嗪-1-羰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,5-dimethylpiperazine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,3-二甲基哌嗪-1-羰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,3-dimethylpiperazine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2-(三氟甲基)哌嗪-1-羰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2-(trifluoromethyl)piperazine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 2-(2,6-二氧代哌啶-3-基)-5-(4-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-羰基)异吲哚啉-1,3-二酮；2-(2,6-dioxopiperidin-3-yl)-5-(4-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-carbonyl)isoindoline-1,3-dione; 5-(4-((4'-氯-[1,1'-联苯]-2-基)甲基)哌嗪-1-羰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-(4-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(4-((4'-氯-[1,1'-联苯]-3-基)甲基)哌嗪-1-羰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-(4-((4'-chloro-[1,1'-biphenyl]-3-yl)methyl)piperazine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(4-((4'-氯-[1,1'-联苯]-4-基)甲基)哌嗪-1-羰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-(4-((4'-chloro-[1,1'-biphenyl]-4-yl)methyl)piperazine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(4-((3-(4-氯苯基)吡啶-4-基)甲基)哌嗪-1-羰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-(4-((3-(4-chlorophenyl)pyridin-4-yl)methyl)piperazine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 2-(2,6-二氧代哌啶-3-基)-5-(4-((4',5,5-三甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-羰基)异吲哚啉-1,3-二酮；2-(2,6-dioxopiperidin-3-yl)-5-(4-((4',5,5-trimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-carbonyl)isoindoline-1,3-dione; 5-(4-((4'-氨基-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-羰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-(4-((4'-amino-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 2-(2,6-二氧代哌啶-3-基)-5-(4-((4'-氟-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-羰基)异吲哚啉-1,3-二酮；2-(2,6-dioxopiperidin-3-yl)-5-(4-((4'-fluoro-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-carbonyl)isoindoline-1,3-dione; 5-(4-((4-(4-氯苯基)-5,6-二氢-2H-吡喃-3-基)甲基)哌嗪-1-羰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-(4-((4-(4-chlorophenyl)-5,6-dihydro-2H-pyran-3-yl)methyl)piperazine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(4-((4'-氯-4,4-二氟-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-羰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-(4-((4'-chloro-4,4-difluoro-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(4-((4'-氯-4-甲氧基-4-甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-羰基)-2-(2,6-二氧代 哌啶-3-基)异吲哚啉-1,3-二酮；5-(4-((4'-chloro-4-methoxy-4-methyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-carbonyl)-2-(2,6-dioxo piperidin-3-yl)isoindoline-1,3-dione; 5-(4-((4-(4-氯苯基)-6,6-二甲基-5,6-二氢-2H-吡喃-3-基)甲基)哌嗪-1-羰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)piperazine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(4-((8-(4-氯苯基)螺[4.5]癸-7-烯-7-基)甲基)哌嗪-1-羰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-(4-((8-(4-chlorophenyl)spiro[4.5]dec-7-en-7-yl)methyl)piperazine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(4-((6-(4-氯苯基)螺[3.5]壬-6-烯-7-基)甲基)哌嗪-1-羰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(3-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-(3-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(8-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-(8-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(3-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-(3-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(6-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-(6-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(5-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-(5-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,5-diazabicyclo[2.2.2]octan-2-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(3-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮；5-(3-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione; 5-(8-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮；5-(8-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione; 5-(3-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮；5-(3-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione; 5-(6-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮；5-(6-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione; 5-(5-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮；5-(5-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,5-diazabicyclo[2.2.2]octan-2-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione; 5-(3-((4'-氯-[1,1'-联苯]-2-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-(3-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(8-((4'-氯-[1,1'-联苯]-2-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-(8-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(3-((4'-氯-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-(3-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(6-((4'-氯-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮； 5-(6-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(5-((4'-氯-[1,1'-联苯]-2-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-(5-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-2,5-diazabicyclo[2.2.2]octan-2-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(3-((4'-氯-[1,1'-联苯]-2-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮；5-(3-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione; 5-(8-((4'-氯-[1,1'-联苯]-2-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮；5-(8-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione; 5-(3-((4'-氯-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮；5-(3-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione; 5-(6-((4'-氯-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮；5-(6-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione; 5-(5-((4'-氯-[1,1'-联苯]-2-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮；5-(5-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-2,5-diazabicyclo[2.2.2]octan-2-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione; 2-(2,6-二氧代哌啶-3-基)-5-(3-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)异吲哚啉-1,3-二酮；2-(2,6-dioxopiperidin-3-yl)-5-(3-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)isoindoline-1,3-dione; 2-(2,6-二氧代哌啶-3-基)-5-(8-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)异吲哚啉-1,3-二酮；2-(2,6-dioxopiperidin-3-yl)-5-(8-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)isoindoline-1,3-dione; 2-(2,6-二氧代哌啶-3-基)-5-(3-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)异吲哚啉-1,3-二酮；2-(2,6-dioxopiperidin-3-yl)-5-(3-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl)isoindoline-1,3-dione; 2-(2,6-二氧代哌啶-3-基)-5-(6-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)异吲哚啉-1,3-二酮；2-(2,6-dioxopiperidin-3-yl)-5-(6-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)isoindoline-1,3-dione; 2-(2,6-二氧代哌啶-3-基)-5-(5-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)异吲哚啉-1,3-二酮；2-(2,6-dioxopiperidin-3-yl)-5-(5-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,5-diazabicyclo[2.2.2]octan-2-yl)isoindoline-1,3-dione; 2-(2,6-二氧代哌啶-3-基)-5-氟-6-(3-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)异吲哚啉-1,3-二酮；2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(3-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)isoindoline-1,3-dione; 2-(2,6-二氧代哌啶-3-基)-5-氟-6-(8-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)异吲哚啉-1,3-二酮；2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(8-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)isoindoline-1,3-dione; 2-(2,6-二氧代哌啶-3-基)-5-氟-6-(3-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)异吲哚啉-1,3-二酮；2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(3-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl)isoindoline-1,3-dione; 2-(2,6-二氧代哌啶-3-基)-5-氟-6-(6-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)异吲哚啉-1,3-二酮；2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(6-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)isoindoline-1,3-dione; 2-(2,6-二氧代哌啶-3-基)-5-氟-6-(5-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)异吲哚啉-1,3-二酮；2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(5-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,5-diazabicyclo[2.2.2]octan-2-yl)isoindoline-1,3-dione; 3-(6-((3-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(6-((3-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((5-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2- 基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(4-((5-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,5-diazabicyclo[2.2.2]octane-2- yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(6-((5-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(6-((5-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,5-diazabicyclo[2.2.2]octan-2-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((5-(4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((5-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(5-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(5-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-氟-5-((4-((4'-氟-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(4-fluoro-5-((4-((4'-fluoro-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((4-((4'-氟-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(4-((4-((4'-fluoro-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(6-((4-((4'-氟-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(6-((4-((4'-fluoro-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-氟-5-((4-(4'-氟-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(4-fluoro-5-((4-(4'-fluoro-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(6-氟-5-((4-(4'-氟-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(6-fluoro-5-((4-(4'-fluoro-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(7-氟-5-((4-(4'-氟-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(7-Fluoro-5-((4-(4'-fluoro-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((4-(4'-氟-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(4-((4-(4'-fluoro-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(6-((4-(4'-氟-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(6-((4-(4'-fluoro-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-氟-5-((3-(4'-氟-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(4-fluoro-5-((3-(4'-fluoro-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(7-氟-5-((3-(4'-氟-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(7-fluoro-5-((3-(4'-fluoro-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((3-(4'-氟-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(4-((3-(4'-fluoro-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(6-((3-(4'-氟-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(6-((3-(4'-fluoro-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(7-((3-(4'-氟-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(7-((3-(4'-fluoro-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((4-((4'-氯-[1,1'-联苯]-2-基)氨基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮； 3-(4-((4-((4'-chloro-[1,1'-biphenyl]-2-yl)amino)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((5-((4'-氯-[1,1'-联苯]-2-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((5-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((5-(4'-氯-[1,1'-联苯]-2-羰基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((5-(4'-chloro-[1,1'-biphenyl]-2-carbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(5-((4'-氯-[1,1'-联苯]-2-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(5-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((5-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((5-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((5-(4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((5-(4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(5-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(5-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-(4'-氟-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)哌嗪-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(4-(4'-fluoro-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperazine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(3-(4'-氟-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)-3,6-二氮杂双环[3.1.1]庚烷-6-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(3-(4'-fluoro-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptane-6-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 2-(2,6-二氧代哌啶-3-基)-4-((4-((4'-氟-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)甲基)异吲哚啉-1,3-二酮；2-(2,6-dioxopiperidin-3-yl)-4-((4-((4'-fluoro-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)methyl)isoindoline-1,3-dione; 5-((5-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-((5-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 2-(2,6-二氧代哌啶-3-基)-5-((4-(4'-氟-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)哌嗪-1-基)甲基)异吲哚啉-1,3-二酮；2-(2,6-dioxopiperidin-3-yl)-5-((4-(4'-fluoro-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)methyl)isoindoline-1,3-dione; 2-(2,6-二氧代哌啶-3-基)-5-((3-(4'-氟-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)异吲哚啉-1,3-二酮；2-(2,6-dioxopiperidin-3-yl)-5-((3-(4'-fluoro-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl)methyl)isoindoline-1,3-dione; 5-(4-((4'-氯-[1,1'-联苯]-2-基)氨基)哌啶-1-羰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-(4-((4'-chloro-[1,1'-biphenyl]-2-yl)amino)piperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 2-(2,6-二氧代哌啶-3-基)-5-(4-(4'-氟-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)哌嗪-1-羰基)异吲哚啉-1,3-二酮；2-(2,6-dioxopiperidin-3-yl)-5-(4-(4'-fluoro-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperazine-1-carbonyl)isoindoline-1,3-dione; 2-(2,6-二氧代哌啶-3-基)-5-(3-(4'-氟-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)-3,6-二氮杂双环[3.1.1]庚烷-6-羰基)异吲哚啉-1,3-二酮；2-(2,6-dioxopiperidin-3-yl)-5-(3-(4'-fluoro-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptane-6-carbonyl)isoindoline-1,3-dione; 3-(5-(((1S,4S)-5-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(((1S,4S)-5-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((1S,4S)-5-(4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(((1S,4S)-5-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((1S,4S)-5-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,5-二氮杂双环[2.2.1] 庚烷-2-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((1S,4S)-5-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,5-diazabicyclo[2.2.1] heptane-2-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(7-(4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)-2,7-二氮杂螺[3.5]壬烷-2-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(7-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(6-(4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)-2,6-二氮杂螺[3.3]庚烷-2-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(6-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(5-(4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)八氢吡咯并[3,4-c]吡咯-2-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(5-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((1S,4S)-5-((4'-氯-[1,1'-联苯]-2-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(((1S,4S)-5-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-氧代-5-((4-((2-苯基嘧啶-5-基)甲基)哌嗪-1-基)甲基)异吲哚啉-2-基)哌啶-2,6-二酮；3-(1-oxo-5-((4-((2-phenylpyrimidin-5-yl)methyl)piperazin-1-yl)methyl)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((1S,4S)-5-(4'-氯-[1,1'-联苯]-2-羰基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(((1S,4S)-5-(4'-chloro-[1,1'-biphenyl]-2-carbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((1S,4S)-5-((4'-氯-[1,1'-联苯]-2-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((1S,4S)-5-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((1S,4S)-5-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(((1S,4S)-5-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((1S,4S)-5-(4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(((1S,4S)-5-(4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 5-(((1S,4S)-5-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-(((1S,4S)-5-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-((1S,4S)-5-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-羰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；5-((1S,4S)-5-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 3-(6-氟-5-((3-(4'-氟-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(6-fluoro-5-((3-(4'-fluoro-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-1,4-二氮杂环庚烷-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,4-diazepan-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(6-(4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)-3,6-二氮杂双环[3.1.1]庚烷-3-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(6-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptane-3-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-((4'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-1,4-二氮杂环庚烷-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-((4-((4'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,4-diazepan-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(7-((5-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(7-((5-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,5-diazabicyclo[2.2.2]octan-2-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(7-((4-(4'-氟-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)哌嗪-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(7-((4-(4'-fluoro-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(3-(4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)-3,6-二氮杂双环[3.1.1]庚烷-6-羰 基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(3-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptane-6-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(3-(4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)-3,8-二氮杂双环[3.2.1]辛烷-8-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；3-(5-(3-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(8-(4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-羰基)-3,8-二氮杂双环[3.2.1]辛烷-3-羰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；和3-(5-(8-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; and 3-(1-氧代-5-((4-(5-苯基吡嗪-2-羰基)哌嗪-1-基)甲基)异吲哚啉-2-基)哌啶-2,6-二酮。3-(1-oxo-5-((4-(5-phenylpyrazine-2-carbonyl)piperazin-1-yl)methyl)isoindolin-2-yl)piperidine-2,6-dione. 如权利要求1至22中任一项所述的式(I)化合物或其盐、对映异构体、非对映异构体、同位素富集类似物、溶剂化物、前药或多晶型物，其是式(I)化合物的盐酸盐、硫酸盐、枸橼酸盐、马来酸盐、甲磺酸盐、柠檬酸盐、乳酸盐、酒石酸盐、富马酸盐、磷酸盐、二氢磷酸盐、焦磷酸盐、偏磷酸盐、草酸盐、丙二酸盐、苯甲酸盐、扁桃酸盐、琥珀酸盐、三氟乙酸盐、羟乙酸盐或对甲苯磺酸盐。A compound of formula (I) or a salt, enantiomer, diastereomer, isotopically enriched analog, solvate, prodrug or polymorph thereof as described in any one of claims 1 to 22, which is a hydrochloride, sulfate, citrate, maleate, methanesulfonate, citrate, lactate, tartrate, fumarate, phosphate, dihydrogenphosphate, pyrophosphate, metaphosphate, oxalate, malonate, benzoate, mandelate, succinate, trifluoroacetate, glycolate or p-toluenesulfonate of a compound of formula (I). 药物组合物，其包含如权利要求1至23中任一项所述的式(I)化合物或其医药学上可接受的盐，及至少一种医药学上可接受的载体。A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 23, and at least one pharmaceutically acceptable carrier. 如权利要求24所述的药物组合物，进一步包括第二治疗剂，例如抗癌剂。The pharmaceutical composition of claim 24, further comprising a second therapeutic agent, such as an anticancer agent. 如权利要求1至23中任一项所述的式(I)化合物或其医药学上可接受的盐或如权利要求24或25所述的药物组合物的用途，其用于制备用以预防及/或治疗与cereblon蛋白相关的疾病或病症的药剂。Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 23 or a pharmaceutical composition as claimed in claim 24 or 25 for preparing a medicament for preventing and/or treating a disease or condition associated with cereblon protein. 如权利要求26所述的用途，其中所述与cereblon蛋白相关的疾病或病症是选自：肿瘤、感染性疾病、炎性疾病、自身免疫性疾病、贫血、出血性休克、移植排斥反应、多器官功能障碍综合征(MODS)、类肉瘤病、成人呼吸窘迫综合征、心血管疾病、里希特氏综合征(Richtersyndrome,RS)、急性肝功能衰竭或糖尿病。The use according to claim 26, wherein the disease or condition associated with the cereblon protein is selected from: tumors, infectious diseases, inflammatory diseases, autoimmune diseases, anemia, hemorrhagic shock, transplant rejection, multiple organ dysfunction syndrome (MODS), sarcoidosis, adult respiratory distress syndrome, cardiovascular disease, Richter syndrome (RS), acute liver failure or diabetes. 如权利要求26所述的用途，其中所述与cereblon蛋白相关的疾病或病症选自由以下组成的群组：骨髓瘤，包括多发性骨髓瘤、浆细胞骨髓瘤、阴燃骨髓瘤、闷烧多发性骨髓瘤；骨髓纤维化；骨髓疾病；骨髓增生异常综合征(MDS)；既往治疗的骨髓增生异常综合征；移植相关的癌症；中性粒细胞减少症；白血病，包括急性髓细胞白血病、慢性粒细胞白血病、B细胞慢性淋巴细胞白血病、与白血病相关的贫血、急性髓性白血病(AML)；淋巴瘤，包括弥漫性大B细胞淋巴瘤、非霍奇金淋巴瘤、霍奇金淋巴瘤、间变性淋巴瘤、间变性大细胞淋巴瘤、CD20阳性淋巴瘤、套细胞淋巴瘤、原发性淋巴瘤、B细胞淋巴瘤、复发性B细胞非霍奇金淋巴瘤、复发性弥漫性大B细胞淋巴瘤、复发性纵隔(胸腺)大B细胞淋巴瘤、原发性纵隔(胸腺)大B细胞淋巴瘤、复发性转化非霍奇金淋巴瘤、难治性B细胞非霍奇金淋巴瘤、难治性弥漫性大B细胞淋巴瘤、难治性原发性纵隔(胸腺)大B细胞淋巴瘤、难治性转化的非霍奇金淋巴瘤；甲状腺癌；黑色素瘤；肺癌，包括肺腺癌、肺鳞癌；炎症性肌纤维母细胞瘤；结直肠癌；肠癌；脑胶质瘤；星形胶质母细胞瘤；卵巢癌；支气管癌；前列腺癌；乳腺癌，包括三阴性乳腺癌、偶发性乳腺癌和考登病患者；胰腺癌；中枢神经系统癌症；神经母细胞瘤；神经胶质瘤；外周神经上皮瘤；髓外浆细胞瘤；浆细胞瘤；胃癌；胃肠道间质瘤； 食道癌；大肠腺癌；食管鳞状细胞癌；肝癌；肾细胞癌；膀胱癌；子宫内膜癌；子宫癌；头颈癌；脑癌；口腔癌；肉瘤，包括横纹肌肉瘤、各种脂肪源性肿瘤、尤文肉瘤/原始神经外胚层瘤(Ewing/PNETs)、和平滑肌肉瘤；尿路上皮癌；基底细胞癌；口腔鳞状细胞癌；胆管癌；骨癌；宫颈癌；皮肤癌；里希特氏综合征(Richter syndrome,RS)；脓毒综合征；自身免疫性疾病，包括类风湿性关节炎、自身免疫性脑脊髓炎、强直性脊柱炎、银屑病、系统性红斑狼疮、多发性硬化症、复发性口腔溃疡、川崎病、多发性肌炎/皮肌炎、干燥综合征、特应性皮炎；角结膜干燥症；炎症性疾病，包括克罗恩病和溃疡性结肠炎、肺炎、骨关节炎、滑膜炎、全身炎症反应综合征、气道炎症、支气管炎；脑型疟疾；感染性疾病，包括病毒性肺炎、艾滋病(AIDS)、COVID-19新型冠状病毒感染、革兰氏阴性菌感染、革兰氏阳性菌感染、结核病等；感染性休克；结核病；细菌性脑膜炎；慢性阻塞性肺疾病；哮喘；出血性休克；器官(包括肾、心脏、肺)或组织移植排斥反应；糖尿病；类肉瘤病；成人呼吸窘迫综合征；贫血；小儿再生障碍性贫血；心血管疾病(例如冠心病、充血性心力衰竭、心肌梗塞、动脉粥样硬化症)；恶病质和败血症休克所致的多器官功能衰竭；或急性肝功能衰竭。The use of claim 26, wherein the disease or condition associated with the cereblon protein is selected from the group consisting of: myeloma, including multiple myeloma, plasma cell myeloma, smoldering myeloma, smoldering multiple myeloma; myelofibrosis; bone marrow disease; myelodysplastic syndrome (MDS); previously treated myelodysplastic syndrome; transplant-related cancer; neutropenia; leukemia, including acute myeloid leukemia, chronic myeloid leukemia, B-cell chronic lymphocytic leukemia, anemia associated with leukemia, acute myeloid leukemia (AML); lymphoma, including diffuse large B-cell lymphoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, anaplastic lymphoma, anaplastic large cell lymphoma, CD20-positive lymphoma, mantle cell lymphoma, primary lymphoma, B-cell lymphoma, relapsed B B-cell non-Hodgkin's lymphoma, relapsed diffuse large B-cell lymphoma, relapsed mediastinal (thymic) large B-cell lymphoma, primary mediastinal (thymic) large B-cell lymphoma, relapsed transformed non-Hodgkin's lymphoma, refractory B-cell non-Hodgkin's lymphoma, refractory diffuse large B-cell lymphoma, refractory primary mediastinal (thymic) large B-cell lymphoma, refractory transformed non-Hodgkin's lymphoma; thyroid cancer; melanoma; lung cancer, including lung adenocarcinoma and lung squamous cell carcinoma; inflammatory myofibroblastic tumor; colorectal cancer; intestinal cancer; glioma; astrocytoma; ovarian cancer; bronchial cancer; prostate cancer; breast cancer, including triple-negative breast cancer, sporadic breast cancer and patients with Cowden's disease; pancreatic cancer; central nervous system cancer; neuroblastoma; glioma; peripheral neuroepithelial tumor; extramedullary plasmacytoma; plasmacytoma; gastric cancer; gastrointestinal stromal tumor; Esophageal cancer; colorectal adenocarcinoma; esophageal squamous cell carcinoma; liver cancer; renal cell carcinoma; bladder cancer; endometrial cancer; uterine cancer; head and neck cancer; brain cancer; oral cancer; sarcomas, including rhabdomyosarcoma, various adipose tumors, Ewing sarcoma/primitive neuroectodermal tumors (Ewing/PNETs), and leiomyosarcoma; urothelial carcinoma; basal cell carcinoma; oral squamous cell carcinoma; bile duct cancer; bone cancer; cervical cancer; skin cancer; Richter's syndrome (Richter's syndrome) sepsis syndrome; autoimmune diseases, including rheumatoid arthritis, autoimmune encephalomyelitis, ankylosing spondylitis, psoriasis, systemic lupus erythematosus, multiple sclerosis, recurrent oral ulcers, Kawasaki disease, polymyositis/dermatomyositis, Sjögren's syndrome, atopic dermatitis; keratoconjunctivitis sicca; inflammatory diseases, including Crohn's disease and ulcerative colitis, pneumonia, osteoarthritis, synovitis, systemic inflammatory response syndrome, airway inflammation, bronchitis; cerebral malaria; infectious diseases, including viral pneumonia, AIDS ), COVID-19 novel coronavirus infection, Gram-negative bacterial infection, Gram-positive bacterial infection, tuberculosis, etc.; septic shock; tuberculosis; bacterial meningitis; chronic obstructive pulmonary disease; asthma; hemorrhagic shock; organ (including kidney, heart, lung) or tissue transplant rejection; diabetes; sarcoidosis; adult respiratory distress syndrome; anemia; aplastic anemia in children; cardiovascular disease (such as coronary heart disease, congestive heart failure, myocardial infarction, atherosclerosis); multiple organ failure caused by cachexia and septic shock; or acute liver failure. 如权利要求1至23中任一项所述的式(I)化合物或其医药学上可接受的盐，其用于预防及/或治疗与cereblon蛋白相关的疾病或病症。A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 23, for use in preventing and/or treating a disease or condition associated with cereblon protein. 如权利要求29所述的式(I)化合物，或其医药学上可接受的盐，其中所述与cereblon蛋白相关的疾病或病症是选自：肿瘤、感染性疾病、炎性疾病、自身免疫性疾病、贫血、出血性休克、移植排斥反应、多器官功能障碍综合征(MODS)、类肉瘤病、成人呼吸窘迫综合征、心血管疾病、里希特氏综合征(Richter syndrome,RS)、急性肝功能衰竭或糖尿病。The compound of formula (I) as claimed in claim 29, or a pharmaceutically acceptable salt thereof, wherein the disease or condition associated with the cereblon protein is selected from: tumors, infectious diseases, inflammatory diseases, autoimmune diseases, anemia, hemorrhagic shock, transplant rejection, multiple organ dysfunction syndrome (MODS), sarcoidosis, adult respiratory distress syndrome, cardiovascular disease, Richter syndrome (RS), acute liver failure or diabetes. 如权利要求29所述的式(I)化合物，或其医药学上可接受的盐，其中所述与cereblon蛋白相关的疾病或病症选自由以下组成的群组：骨髓瘤，包括多发性骨髓瘤、浆细胞骨髓瘤、阴燃骨髓瘤、闷烧多发性骨髓瘤；骨髓纤维化；骨髓疾病；骨髓增生异常综合征(MDS)；既往治疗的骨髓增生异常综合征；移植相关的癌症；中性粒细胞减少症；白血病，包括急性髓细胞白血病、慢性粒细胞白血病、B细胞慢性淋巴细胞白血病、与白血病相关的贫血、急性髓性白血病(AML)；淋巴瘤，包括弥漫性大B细胞淋巴瘤、非霍奇金淋巴瘤、霍奇金淋巴瘤、间变性淋巴瘤、间变性大细胞淋巴瘤、CD20阳性淋巴瘤、套细胞淋巴瘤、原发性淋巴瘤、B细胞淋巴瘤、复发性B细胞非霍奇金淋巴瘤、复发性弥漫性大B细胞淋巴瘤、复发性纵隔(胸腺)大B细胞淋巴瘤、原发性纵隔(胸腺)大B细胞淋巴瘤、复发性转化非霍奇金淋巴瘤、难治性B细胞非霍奇金淋巴瘤、难治性弥漫性大B细胞淋巴瘤、难治性原发性纵隔(胸腺)大B细胞淋巴瘤、难治性转化的非霍奇金淋巴瘤；甲状腺癌；黑色素瘤；肺癌，包括肺腺癌、肺鳞癌；炎症性肌纤维母细胞瘤；结直肠癌；肠癌；脑胶质瘤；星形胶质母细胞瘤；卵巢癌；支气管癌；前列腺癌；乳腺癌，包括三阴性乳腺癌、偶发性乳腺癌和考登病患者；胰腺癌；中枢神经系统癌症；神经母细胞瘤；神经胶质瘤；外周神经上皮瘤；髓外浆细胞瘤；浆细胞瘤；胃癌；胃肠道间质瘤；食道癌；大肠腺癌；食管鳞状细胞癌；肝癌；肾细胞癌；膀胱癌；子宫内膜癌；子宫癌；头颈癌；脑癌；口腔癌；肉瘤，包括横纹肌肉瘤、各种 脂肪源性肿瘤、尤文肉瘤/原始神经外胚层瘤(Ewing/PNETs)、和平滑肌肉瘤；尿路上皮癌；基底细胞癌；口腔鳞状细胞癌；胆管癌；骨癌；宫颈癌；皮肤癌；里希特氏综合征(Richter syndrome,RS)；脓毒综合征；自身免疫性疾病，包括类风湿性关节炎、自身免疫性脑脊髓炎、强直性脊柱炎、银屑病、系统性红斑狼疮、多发性硬化症、复发性口腔溃疡、川崎病、多发性肌炎/皮肌炎、干燥综合征、特应性皮炎；角结膜干燥症；炎症性疾病，包括克罗恩病和溃疡性结肠炎、肺炎、骨关节炎、滑膜炎、全身炎症反应综合征、气道炎症、支气管炎；脑型疟疾；感染性疾病，包括病毒性肺炎、艾滋病(AIDS)、COVID-19新型冠状病毒感染、革兰氏阴性菌感染、革兰氏阳性菌感染、结核病等；感染性休克；结核病；细菌性脑膜炎；慢性阻塞性肺疾病；哮喘；出血性休克；器官(包括肾、心脏、肺)或组织移植排斥反应；糖尿病；类肉瘤病；成人呼吸窘迫综合征；贫血；小儿再生障碍性贫血；心血管疾病(例如冠心病、充血性心力衰竭、心肌梗塞、动脉粥样硬化症)；恶病质和败血症休克所致的多器官功能衰竭；或急性肝功能衰竭。The compound of formula (I) as claimed in claim 29, or a pharmaceutically acceptable salt thereof, wherein the disease or condition associated with the cereblon protein is selected from the group consisting of: myeloma, including multiple myeloma, plasma cell myeloma, smoldering myeloma, smoldering multiple myeloma; myelofibrosis; bone marrow disease; myelodysplastic syndrome (MDS); previously treated myelodysplastic syndrome; transplant-related cancer; neutropenia; leukemia, including acute myeloid leukemia, chronic myeloid leukemia, B-cell chronic lymphocytic leukemia, anemia associated with leukemia, acute myeloid leukemia (AML); lymphoma, including diffuse large B-cell lymphoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, anaplastic lymphoma, anaplastic large cell lymphoma, CD20-positive lymphoma, mantle cell lymphoma, primary lymphoma, B-cell lymphoma, relapsed B-cell non-Hodgkin's lymphoma, relapsed diffuse large B-cell lymphoma , recurrent mediastinal (thymic) large B-cell lymphoma, primary mediastinal (thymic) large B-cell lymphoma, recurrent transformed non-Hodgkin's lymphoma, refractory B-cell non-Hodgkin's lymphoma, refractory diffuse large B-cell lymphoma, refractory primary mediastinal (thymic) large B-cell lymphoma, refractory transformed non-Hodgkin's lymphoma; thyroid cancer; melanoma; lung cancer, including lung adenocarcinoma and lung squamous cell carcinoma; inflammatory myofibroblastic tumor; colorectal cancer; intestinal cancer; brain glioma; astrocytoma cell tumors; ovarian cancer; bronchogenic cancer; prostate cancer; breast cancer, including triple-negative breast cancer, sporadic breast cancer, and patients with Cowden disease; pancreatic cancer; central nervous system cancer; neuroblastoma; glioma; peripheral neuroepithelial tumor; extramedullary plasmacytoma; plasmacytoma; gastric cancer; gastrointestinal stromal tumors; esophageal cancer; colorectal adenocarcinoma; esophageal squamous cell carcinoma; liver cancer; renal cell carcinoma; bladder cancer; endometrial cancer; uterine cancer; head and neck cancer; brain cancer; oral cancer; sarcomas, including rhabdomyosarcoma, various lipid tumors, Ewing sarcoma/primitive neuroectodermal tumors (Ewing/PNETs), and leiomyosarcoma; urothelial carcinoma; basal cell carcinoma; oral squamous cell carcinoma; bile duct cancer; bone cancer; cervical cancer; skin cancer; Richter's syndrome (Richter sepsis syndrome; autoimmune diseases, including rheumatoid arthritis, autoimmune encephalomyelitis, ankylosing spondylitis, psoriasis, systemic lupus erythematosus, multiple sclerosis, recurrent oral ulcers, Kawasaki disease, polymyositis/dermatomyositis, Sjögren's syndrome, atopic dermatitis; keratoconjunctivitis sicca; inflammatory diseases, including Crohn's disease and ulcerative colitis, pneumonia, osteoarthritis, synovitis, systemic inflammatory response syndrome, airway inflammation, bronchitis; cerebral malaria; infectious diseases, including viral pneumonia, AIDS ), COVID-19 novel coronavirus infection, Gram-negative bacterial infection, Gram-positive bacterial infection, tuberculosis, etc.; septic shock; tuberculosis; bacterial meningitis; chronic obstructive pulmonary disease; asthma; hemorrhagic shock; organ (including kidney, heart, lung) or tissue transplant rejection; diabetes; sarcoidosis; adult respiratory distress syndrome; anemia; aplastic anemia in children; cardiovascular disease (such as coronary heart disease, congestive heart failure, myocardial infarction, atherosclerosis); multiple organ failure caused by cachexia and septic shock; or acute liver failure. 治疗或预防与cereblon蛋白相关的疾病或病症的方法，其包括向受试者施用治疗有效量的如权利要求1-23中任一项所述的式(I)化合物，或其医药学上可接受的盐，或如权利要求24或25所述的药物组合物。A method for treating or preventing a disease or disorder associated with cereblon protein, comprising administering to a subject a therapeutically effective amount of a compound of formula (I) as described in any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 24 or 25. 如权利要求32所述的方法，其中所述与cereblon蛋白相关的疾病或病症是选自：肿瘤、感染性疾病、炎性疾病、自身免疫性疾病、贫血、出血性休克、移植排斥反应、多器官功能障碍综合征(MODS)、类肉瘤病、成人呼吸窘迫综合征、心血管疾病、里希特氏综合征(Richtersyndrome,RS)、急性肝功能衰竭或糖尿病。The method of claim 32, wherein the disease or condition associated with the cereblon protein is selected from: tumors, infectious diseases, inflammatory diseases, autoimmune diseases, anemia, hemorrhagic shock, transplant rejection, multiple organ dysfunction syndrome (MODS), sarcoidosis, adult respiratory distress syndrome, cardiovascular disease, Richter syndrome (RS), acute liver failure or diabetes. 如权利要求32所述的方法，其中所述与cereblon蛋白相关的疾病或病症选自由以下组成的群组：骨髓瘤，包括多发性骨髓瘤、浆细胞骨髓瘤、阴燃骨髓瘤、闷烧多发性骨髓瘤；骨髓纤维化；骨髓疾病；骨髓增生异常综合征(MDS)；既往治疗的骨髓增生异常综合征；移植相关的癌症；中性粒细胞减少症；白血病，包括急性髓细胞白血病、慢性粒细胞白血病、B细胞慢性淋巴细胞白血病、与白血病相关的贫血、急性髓性白血病(AML)；淋巴瘤，包括弥漫性大B细胞淋巴瘤、非霍奇金淋巴瘤、霍奇金淋巴瘤、间变性淋巴瘤、间变性大细胞淋巴瘤、CD20阳性淋巴瘤、套细胞淋巴瘤、原发性淋巴瘤、B细胞淋巴瘤、复发性B细胞非霍奇金淋巴瘤、复发性弥漫性大B细胞淋巴瘤、复发性纵隔(胸腺)大B细胞淋巴瘤、原发性纵隔(胸腺)大B细胞淋巴瘤、复发性转化非霍奇金淋巴瘤、难治性B细胞非霍奇金淋巴瘤、难治性弥漫性大B细胞淋巴瘤、难治性原发性纵隔(胸腺)大B细胞淋巴瘤、难治性转化的非霍奇金淋巴瘤；甲状腺癌；黑色素瘤；肺癌，包括肺腺癌、肺鳞癌；炎症性肌纤维母细胞瘤；结直肠癌；肠癌；脑胶质瘤；星形胶质母细胞瘤；卵巢癌；支气管癌；前列腺癌；乳腺癌，包括三阴性乳腺癌、偶发性乳腺癌和考登病患者；胰腺癌；中枢神经系统癌症；神经母细胞瘤；神经胶质瘤；外周神经上皮瘤；髓外浆细胞瘤；浆细胞瘤；胃癌；胃肠道间质瘤；食道癌；大肠腺癌；食管鳞状细胞癌；肝癌；肾细胞癌；膀胱癌；子宫内膜癌；子宫癌；头颈癌；脑癌；口腔癌；肉瘤，包括横纹肌肉瘤、各种脂肪源性肿瘤、尤文肉瘤/原始神经外胚 层瘤(Ewing/PNETs)、和平滑肌肉瘤；尿路上皮癌；基底细胞癌；口腔鳞状细胞癌；胆管癌；骨癌；宫颈癌；皮肤癌；里希特氏综合征(Richter syndrome,RS)；脓毒综合征；自身免疫性疾病，包括类风湿性关节炎、自身免疫性脑脊髓炎、强直性脊柱炎、银屑病、系统性红斑狼疮、多发性硬化症、复发性口腔溃疡、川崎病、多发性肌炎/皮肌炎、干燥综合征、特应性皮炎；角结膜干燥症；炎症性疾病，包括克罗恩病和溃疡性结肠炎、肺炎、骨关节炎、滑膜炎、全身炎症反应综合征、气道炎症、支气管炎；脑型疟疾；感染性疾病，包括病毒性肺炎、艾滋病(AIDS)、COVID-19新型冠状病毒感染、革兰氏阴性菌感染、革兰氏阳性菌感染、结核病等；感染性休克；结核病；细菌性脑膜炎；慢性阻塞性肺疾病；哮喘；出血性休克；器官(包括肾、心脏、肺)或组织移植排斥反应；糖尿病；类肉瘤病；成人呼吸窘迫综合征；贫血；小儿再生障碍性贫血；心血管疾病(例如冠心病、充血性心力衰竭、心肌梗塞、动脉粥样硬化症)；恶病质和败血症休克所致的多器官功能衰竭；或急性肝功能衰竭。 The method of claim 32, wherein the disease or condition associated with the cereblon protein is selected from the group consisting of: myeloma, including multiple myeloma, plasma cell myeloma, smoldering myeloma, smoldering multiple myeloma; myelofibrosis; bone marrow disease; myelodysplastic syndrome (MDS); previously treated myelodysplastic syndrome; transplant-related cancer; neutropenia; leukemia, including acute myeloid leukemia, chronic myeloid leukemia, B-cell chronic lymphocytic leukemia, anemia associated with leukemia, acute myeloid leukemia (AML); lymphoma, including diffuse large B-cell lymphoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, anaplastic lymphoma, anaplastic large cell lymphoma, CD20-positive lymphoma, mantle cell lymphoma, primary lymphoma, B-cell lymphoma, relapsed B-cell non-Hodgkin's lymphoma, relapsed diffuse large B-cell lymphoma, relapsed mediastinal (thymic) large B-cell lymphoma, Primary mediastinal (thymic) large B-cell lymphoma, relapsed transformed non-Hodgkin's lymphoma, refractory B-cell non-Hodgkin's lymphoma, refractory diffuse large B-cell lymphoma, refractory primary mediastinal (thymic) large B-cell lymphoma, refractory transformed non-Hodgkin's lymphoma; thyroid cancer; melanoma; lung cancer, including lung adenocarcinoma and lung squamous cell carcinoma; inflammatory myofibroblastic tumor; colorectal cancer; intestinal cancer; brain glioma; astrocytoma; ovarian cancer; bronchial cancer; prostate cancer; Breast cancer, including triple-negative breast cancer, incidental breast cancer, and patients with Cowden disease; pancreatic cancer; central nervous system cancers; neuroblastoma; glioma; peripheral neuroepithelial tumors; extramedullary plasmacytoma; plasmacytoma; gastric cancer; gastrointestinal stromal tumors; esophageal cancer; colorectal adenocarcinoma; esophageal squamous cell carcinoma; liver cancer; renal cell carcinoma; bladder cancer; endometrial cancer; uterine cancer; head and neck cancer; brain cancer; oral cancer; sarcomas, including rhabdomyosarcoma, various adipose tumors, Ewing sarcoma/primitive neuroectodermal tumors (Ewing/PNETs), and leiomyosarcoma; urothelial carcinoma; basal cell carcinoma; oral squamous cell carcinoma; bile duct cancer; bone cancer; cervical cancer; skin cancer; Richter's syndrome (Richter's syndrome); sepsis syndrome; autoimmune diseases, including rheumatoid arthritis, autoimmune encephalomyelitis, ankylosing spondylitis, psoriasis, systemic lupus erythematosus, multiple sclerosis, recurrent oral ulcers, Kawasaki disease, polymyositis/dermatomyositis, Sjögren's syndrome, atopic dermatitis; keratoconjunctivitis sicca; inflammatory diseases, including Crohn's disease and ulcerative colitis, pneumonia, osteoarthritis, synovitis, systemic inflammatory response syndrome, airway inflammation, bronchitis; cerebral malaria; infectious diseases, including viral pneumonia, AIDS ), COVID-19 novel coronavirus infection, Gram-negative bacterial infection, Gram-positive bacterial infection, tuberculosis, etc.; septic shock; tuberculosis; bacterial meningitis; chronic obstructive pulmonary disease; asthma; hemorrhagic shock; organ (including kidney, heart, lung) or tissue transplant rejection; diabetes; sarcoidosis; adult respiratory distress syndrome; anemia; aplastic anemia in children; cardiovascular disease (such as coronary heart disease, congestive heart failure, myocardial infarction, atherosclerosis); multiple organ failure caused by cachexia and septic shock; or acute liver failure.
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